Immunology Final PHAR525
Drug Related risk for HS reactions: - Dose: - Duration: - Route - Structure:
- Dose: higher - Duration: longer - Route: topical > IV = IM > oral - Structure: large complex molecules that can host antigens on their own or small molecules + carrier protein
Vancomycin hypersensitivity is most commonly associated with a rapid infusion of vancomycin, given this, how can you prevent vancomycin HS?
- pre-treat with diphenhydramine (H1-blocker) if the patient is undergoing a prolonged infusion (ex: surgery)-- remember its due to direct release of histamine from mast cells - infuse at slower rate - less common given oral and intraperitoneal admin
What to do if patients report a Type I allergy to penicillin?
- take detailed allergy/med history --> identify specific agents and determine cross-reactivity - consider skin testing: determine extent of penicillin allergy --can only determine if a pt has an immediate (Type I) hypersensitivity reaction - safe to avoid most β-lactam antibiotics (but
MOA of Type III reactions? (how do they occur)
- when antibody-antigen complexes (immune complexes) are formed in the blood and thereafter are depositing in tissues causing inflammation. - Local Inflammation: influx of neutrophils causing further tissue destruction
How can having a reported-penicillin allergy especially if it is not a true allergy be potentially harmful?
--> get prescribed penicillins that are - less effective - more expensive - have a broader spectrum of activity than necessary
how long after drug exposure does it take for the tissue effects of histamine to onset
1-2 mins --> hence, it has immediate effects (increased capillary permeability, bronchoconstriction, hyper-secretion of mucus glands: runny nose, flemy cough)
4 patient related risk factors for hypersensitivity reactions
1. Age: adults > kids (children less likely to be exposed to sensitizing drugs) 2. Gender: women more likely than men 3. Genetics: HLA molecules present to T-cells (each individual's HLA are different) 4. History of drug allergy: increases risk of HS reactions, can also be class-wide (penicillins, β-lactams)
5 main mechanisms by which drugs may cause fever
1. Altered thermoregulatory mechanism: increase heat production or prevent the body from getting rid of heat - Altered central temperature regulation - Interference with heat dissipation - ex: increase metabolic rate or act directly on hypothalamus, dissipation of heat due to stimulation of sweat glands, 2. Administration-related - Ex: amphotericin B (inherent pyrogenicity), vancomycin HS (direct release of histamine from mast cells/basophils), vaccines (contain bacterial or viral pyrogens) 3. Pharmacologic action of drug -Ex: some antibiotics cause release of bacterial pyrogens - most commonly in tx of syphillus&lyme disease - chemotherapeutic agents: cause the release of endogenous pyrogens when they destroy cancer cells 4. Idiosyncratic reactions Malignant hyperthermia, neuroleptic malignant syndrome (often associated with anesthetic agents) -- we do not know why a particular person would experience - may be an unidentified genetic component
4 Drug-related risk factors for hypersensitivity reactions
1. Higher Dose 2. Longer Duration of a single dose 3. ROA: Topical > IV > IM > oral 4. Structure: larger, more complex molecules that can service antigens on their own are more likely to be immunogenic OR small molecules attached to carrier proteins can elicit immunologic response
What are the major effects of histamine (3 main)
1. Increased capillary permeability: redness, inflammation 2. Bronchoconstriction: SOB 3. Hyper-secretion of mucus glands: runny nose, flemy cough
2 SERIOUS cutaneous types of Type IV Hypersensitivity (T-cell mediated reactions)
1. Stevens Johnson Syndrome 2. Topical Epidermal Necrolysis
Steps in treating anaphylaxis
1. Stop the offending agent 2. Do whatever is needed to keep the patient alive - monitor vital signs, heart function, lung function - give O2 if needed - give Epinephrine because it causes bronchodilation making it easier to breathe, and vasoconstriction which helps increase the patient's blood pressure - give IV fluids if needed to maintain BP - give pt CCS to reduce the risk of late-phase reaction
Why is it important to suspect drug-induced fever when patients have a fever of unknown origin? (2 reasons)
1. most patients will be suspected of having an infection even if they do not have accompanying signs or symptoms of infection which might lead to overuse of antibiotic medications which can lead to antibiotic resistance 2. drug fever may precede a more serious drug adverse event
Which gen of cephalosporins are the most likely to be cross-reactive in patients with penicillins?
1st and 2nd generation cephalosporins (if their side chains are similar enough) -- Cephalexin, Cefadroxil
What is the first step in treating an anaphylactic-type reaction?
STOP THE OFFENDING DRUG! -- d/c therapy
Type IV reactions
T-cell mediated reactions: mediated by T-cells without involvement from antibodies: antigens are presented by APCs to Helper-T cells which release cytokines that attract effector cells
Why would you give CCS to a pt experiencing an anaphylactic type reaction if they do not help immediately?
They are given to reduce the risk of the pt developing a late-phase reaction: the risk of dying from anaphylaxis is greatest within the first few hours, however even after an apparent recovery, anaphylaxis may reoccur 6-8 hour after the antigen was exposed, because of the possibility of these late-phase reactions it is a good idea to give CCS and patients should be observed for at least 12 hours after they experience an anaphylaxis
Small compounds (<10kDa) cannot serve as antigens on their own, therefore cannot elicit immunologic responses on their own, how then are small molecule drugs still able to invoke immunologic response?
They can be covalently bound to carrier proteins known as haptens, when bound together they can be recognized by (are large enough to be recognized by) the immune system - provoke response
urticaria
allergic reaction of the skin characterized by the eruption of pale red, elevated patches called wheals or hives
which cells play a role in non-immediate development of a HS reaction?
eosinophils
Contact allergens that can provoke a type IV reacton?
poison ivy, nickel in jewelry/belt buckles, fragrances, preservatives
Purpose of histamine in penicillin allergic reaction
positive control - expect for rxn to occur
Type I reactions normally occur when ?
prior drug exposure and sensitization has occurred (IgE recognized and planted on basophils/mast cell surface) but lack of sensitization does not preclude Type I reactions.
PPD skin test
test performed on individuals who have recently been exposed to tuberculosis
NSAIDs, Penicillins, Insulins
the most commonly reported drugs associated with Anaphylaxis
What is the most common and least severe symptom of a Type I reaction?
urticaria: wheel and flair reactions --> rapid development of irregular pruritic blanched papules --> hives - wheels -- can resemble mosquito/insect bite
major determinant of allergy in penicillin skin testing? (the part of the drug molecule that is most involved with penicillin allergic reactions)
Benzylpenicilloyl polylysine
Pencillins, Cephalosporins and Carbapenems are all antibiotics of which class?
Beta-Lactams: R-groups provide variation in their spectrum of activity against different bacteria, their DOA, and contributes to their cross-reactivity potential in the setting of an allergy
Allergic reactions to penicillin occur in 1% of treatment courses, however most people who say they have an allergy to penicillin actually don't actually have one . . . why?
Even with a well documented allergy, hypersensitivity may not persist over time due to loss of anti-Penicillin IgE antibodies --> you can lose up to 80% over 10 years - can be Type I-IV as well as idiopathic --> mechanism unknown
Major determinant of penicillin allergic reaction? minor determinant?
Major: benzylpenicilloyl polylysine Minor: Penicillin G
Long-term side effects of prednisone
Hypertension Hyperlipidemia Osteoporosis
Where is histamine stored
basophils and mast cell granules
What cells produce leukotrienes
basophils and mast cells
Which cells play a role in immediate development of a HS reaction?
basophils and mast cells
Why are Type II reactions also called cytotoxic reactions?
because they result in antibody-mediated cell destruction: the hapten (drug on carrier protein) binds to a target cell, typically a blood cell (WBC, RBC, platelet), IgG or IgM antibodies then bind to the hapten (the antigen on the cell surface), these IgG or IgM antibodies then recruit complement or NK cells resulting in cell lysis and destruction.
Rapid fluid tests use which body fluids to sample / test
blood or oral fluids
antimetabolite side effects
bone marrow suppression, GI side effects (N/V, diarrhea)
CAR-T cell therapy Place in therapy
- Relapsed or refractory B-cell ALL - Relapse or refractory diffuse large B-cell lymphoma
How long on average does it take toxicities of checkpoint inhibitors to resolve after stopping therapy and initiating supplemental treatment ?
about 6 weeks! (2 months ish)
AIDS
acquired immune deficiency syndrome
Symptoms of Type I HS reactions are related to
activation of mast cells and basophils after drug exposure
immune system that is slow and specific
adaptive immune system: NK cells, T-cells, B-cells
MOA of Anaphylactoid reactions if they do not involve antibodies? (they are pseudo-allergic reactions)
administration of a drug leads to a direct release of mediators from effector cells
Antibodies
proteins that are produced by the plasma cells which come from our B cells
Reaction that resembles an allergic reaction but is not mediated by the immunes system
pseudoallergic reaction
Murine mAbs
"mo" suffix 100% mouse derived - most likely to cause infusion related reactions - most foreign
Human mAbs
"u" suffix - 100% human derived mAbs - least likely to cause infusion related reactions
Chimeric mAbs
"xi" suffix - largely human derived but still have a significant portion mouse - still possess large potential to cause infusion reaction (Recognized as foreign)
Humanized mAbs
"zu" suffix mAbs that are mostly human, small portion mouse-derived - less likely to cause infusion reactions that chimeric or murine
Genes that can be involved in development of autoimmune disease
- AIRE genes - Fas ligand gene - MHC genes *more often it is a multigenetic process where genes that control apoptosis, the expression of cytokines and co-stimulatory molecules / signaling are involved **
In order to classify a reaction as drug-induced vasculitis, 3/5 of the following criteria must be present: - - - - -
- Age of onset > 16 - On medication associated with drug-induced vasculitis: cefaclor, hydralazine, allopurinol, G-CSF, GM-CSF, minocycline, penicillamine, phenytoin, isotretinoin, methotrexate - Palpable purpura (slightly elevated purpuric lesions over 1 or more area of the skin) - Maculopapular rash (flat and raised lesions of various sizes on one or more bodies of the skin) - Biopsy including arteriole and venules: granulocytes found in biopsy
Symptomatic treatment of serum sickness? (Hint: fever, malaise, lymphadenopathy, rashes, joint pain = symptoms)
- Antihistamines - Antipyretics - Corticosteroids (if severe)
Two agents that a Calcineurin Inhibitor (signal 1 blocker) could be combined with in an immunosuppressive maintenance regimen? Fill in the blank Calcineurin + _______ +/- Prednisone Calcineurin + _______ +/- Prednisone
- Antimetabolite (AZA, mycophenolate) - signal 3 inhibitor - mTOR Inhibitor (sirolimus, everolimus): signal 3 blocker
Pre-rejection screenings
- Blood-Typing - HLA Crossmatching (HLA): testing that can determine specific immune reactions between the donor and recipient: a test looks to see if the transplant recipient already has antibodies that will recognize the donor organ (and attack it) -If antibody is present for the donor's HLA, this is called a positive crossmatch
Clinical definition of AIDS
- CD4 cell count < 200 cells/mm3 (14%) - When CD4 cell count drops below < 200 --> patients have a very High risk of opportunistic infections -
T-cell types and functions
- CD4 helper T cells: activate cytokines (which can also activate B cells) - CD8 cytotoxic T cells: directly cytotoxic
Which signal of the T-cell response do the following drug classes inhibit: - Calcineurin Inhibitors: - mTOR inhibitors: - Belatacept: - Antimetabolites:
- Calcineurin Inhibitors: Signal 1 (Recognition) - mTOR inhibitors: Signal 3 (proliferation) - Belatacept: Signal 2 (co-stimulation) - Antimetabolites: Signal 3 (proliferation)
mTOR inhibitors (signal 3 inhibitors) can be combined with? +/- Prednisone
- Calcineurin inhibitors - signal 1 - Antimetabolites - signal 3
Clinical presentation of Celiac's Disease
- Crampy abdominal pain - Diarrhea - Steatorrhea: presence of excessive fat in the feces - Failure to thrive, apathy, muscle wasting, weight loss - Dermatitis herpetiformis: itchy, blistery skin rash in 20-25% patients (often mistaken for eczema)
When does drug fever onset typically?
- Days-3 weeks (6-45 days) after a drug has been started - lag time can be as long as several years - within hours of a re-challenge in a previously sensitized patient
Cyclosporine eye drops (Restasis) - Drug Class: - Pt Counseling: - SE:
- Drug Class: Interleukin-2 (IL-2) inhibitor Counseling: - May take 3-6 months to be effective - Remove contact lenses prior to use - SE: burning sensation, blurred vision, irritation Rx eye drops used to treat dry eyes due to Sjogren syndrome
Primary treatment of Celiac's disease
- Eliminate gluten from diet: wheat, barley, rye - may need Vitamin supplements if nutritional deficiency is severe - may need steroids if intestinal damage/inflammation is severe
What patients will require less immunosuppressive regimens
- Infection history: any significant infection will put the patient at higher risk for infection if given an immunosuppressive medication - caution - History of malignancy (potential myelosuppression?) - Poor kidney function (poor drug clearance)
Describe the CD4+ count in terms of HIV Infection stages: - First Exposure: - Acute Stage (soon after): - After 50% decrease in CD4 count: - After Seroconversion: given no tx is given
- First Exposure: CD4 count is normal, around 1000 (b/w 800-1200) - Acute Stage (soon after): CD4 count drops dramatically (about 50%) - After 50% decrease in CD4 count: CD4 count begins to increase slightly due to potential antibody development-- your body is now trying to fight off some of the infection (making more CD4 cells) - After Seroconversion (after developing antibodies to a detectable extent): CD4 cells will continue to drop but not as dramatically as they did in the acute stage--> there is a reason as to why this occurs if you are not treated (
Describe the HIV Viral Load in terms of HIV Infection stages: - First Exposure: - Acute Stage (10 days after exposure): - After 50% decrease in CD4 count: - After Seroconversion: given no tx is given
- First Exposure: no HIV in body (detectable) - Acute Stage (10 days after exposure): very high spike of HIV (high spike in blood plasma) - After 50% decrease in CD4 count: viral load begins to decrease (after acute infection) because CD8 cells are providing some stabilization: lysing some of the infected cells and inhibiting further viral replication/the ability for HIV to infection more of your immune cells --> gives your body a fighting chance - After Seroconversion: Viral load will continually increase if treatment is not given
Nucleic Acid Test (NAT, HIV RNA Test, Viral Load Test): - Function: - Clinical Usage: - Diagnostic Usage:
- Function: Detects the amount of HIV in every mL of one's blood, not used as a diagnostic tool. - Clinical Usage: to determine the efficacy of therapy (is it lowering viral load effectively or preventing disease progression) Diagnostic Usage: Used as an adjunctive tool in patients who may still be in the acute phase of infection where no antigens or antibodies may be detected by any other diagnostic test (≤10 days after exposure)
What effector role do the following Antigen-Presenting cells play in mediating allergic reactions: - Granulocytes: - Macrophages
- Granulocytes: contain granules of different compounds that mediate immune activities - Macrophages: process the drugs as the antigen for recognition by T and B-cells
Which 3 types of HLA are the most important in Transplant?
- HLA-A (class I) - HLA-B (class I) - HLA-DR (class II)
VEGF Inhibitor Toxicities: prevention and management
- HTN: Inhibit the release of nitric oxide thereby inhibiting the ability to vasodilate, effectively resulting in vasoconstriction which will increase BP most important toxicity to remember with VEGF inhibitors - Proteinuria/nephrotic syndrome - Thrombosis - Bleeding: Optimize HTN management - d/c permanently if occurs as Grade 3 or 4 - Wound dehiscence - d/c permanently - GI perforation - d/c permanently
MOA of Blinatumomab, a bispecific T-cell Engager (BiTE)
- Has a CD3 targeted antibody on one side and a CD19 targeted antibody on the other side - The CD3 Target: on the T-cell, therefore a Blinatumomab drug can attach to the T-cell at the CD3 marker - The CD19 Target: on the tumor cell, due to the fact that it has both CD3 marker on the T cell and the CD19 marker on the Tumor cell --> it can effectively bring the T-cell to the tumor cell - Ultimately, mediates the formation of a synapse between a T-cell and a Tumor Cell --> up-regulates all of the processes needed in order for that T-cell to produce cytolytic proteins, inflammatory cytokines and ultimately result in direct cell-lysis of any CD19 positive cell
Fv Region of monoclonal antibodies
- Highly variable region - responsible for binding to tumor marker
Data supporting genetics as an etiology for autoimmune disease
- Identical twin data - Animal data - ex: Non-obese diabetic mice very likely to get diabetes
Interferon-alpha (IFN) - Immunotherapy type: - MOA: - Indication: - Toxicities: - Management of toxicities
- Immunotherapy type: Cytokine therapy - MOA: induces the expression of many genes, inhibits protein synthesis, and exerts a number of different effects on diverse cellular processes: not curative for any tumor but can induce partial responses for follicular lymphoma, hairy cell leukemia, CML, melanoma, Kaposi's sarcoma - Indication: generally not the treatment of choice for any cancer -- slow, durable response but highly toxic therefore newer agents that take less time to work and are less toxic are preferred - Toxicities/Management: Delusions/hallucinations: Lorazepam, haloperidol Depression: pre-medicate with antidepressants (if high risk) Fatigue: hydration Flu-like symptoms: hydration, analgesics, antiemetics, bedtime administration Anorexia: high-protein supplements, multivitamins Psoriasis: pharmacologic or phototherapy - Hepatotoxicity: avoid alcohol consumption - CARDIOTOXICITY: consider rate-controlling agent
Interleukin-2 (Aldesleukin) - Immunotherapy type: - MOA: - Indication: - Toxicities: - Management of toxicities
- Immunotherapy type: major Cytokine therapy available - MOA: mimics our endogenous supply of IL-2 (recombinant form of endogenous IL-2), thereby acts by increasing the number of T-cells that are around, activates them and boosts more T-cell production. Ultimately, all of the above provides the T-cell resource that is needed to attack the cancer cell effectively - Indication: used to be one of the few tx we had for metastatic solid tumors that could produce a complete response in patients - durable for decades without further treatment --slow, durable response but highly toxic therefore newer agents that take less time to work and are less toxic are preferred - Toxicities/Management of toxicities: Hypotension/oliguria/rising SCr: fluid, vasopressors Metabolic acidosis: sodium bicarbonate Dyspnea and peripheral edema: Diuretics Fever/chills/muscle aches: pre-medicate with APAP, NSAIDs --> treat with Meperidine (rigors/chills) N/V: pre-medicate and treat with 5HT3-RA(ondansetron) or Olanzapine (dopamine antagonist) do not use steroids- suppress more Skin, rash, pruritus: antihistamines, emollients Cardiotoxicity: consider rate-controlled agent
When do we use HIV RNA Test: - In general: - From a diagnostic perspective
- In general: Typically only used for to assess the effectiveness of HIV therapy - From a diagnostic perspective: used when HIV-antibody test was negative and you think the pt may be in the acute HIV infection period
Most common signs and symptoms of infections regardless of whether its an OI or any other infection:
- Increased WBC Count - Increased temperature (aka pyrexia)
Stages of SJS and TEN (severe cutaneous Type IV reactions)
- Initially: non-specific symptoms such as fever, sore throat, cough - Then: rash and blister on skin: face, lips, eyes, genitals - the more BSA effected, the higher the risk of mortality
Apoptotic Defects as an endogenous mechanism of autoimmunity
- Irregular FasL and TNFα activity- proteins involved with the extracellular pathway of apoptosis - Defects in the clearance of apoptotic material which may lead to an immune response (ex: Lupus ---> defects in clearance of apoptotic debris has been observed) -- therefore autoimmunity not only related to generation of self-reactance but also how it is cleared
PERIPHERAL TOLERANCE Ignorance
- Lack of productive encounter between lymphocyte and antigen (similar to some of the central tolerance mechanisms) - Can be overcome by changing where or how much antigen is available
Supportive care in GBS
- Monitoring blood pressure/respiratory function - Prevention of blood clots - Physical therapy and psychosocial support
How does mortality occur in SJS/TEN? What does this say about the proper treatment of SJS or TEN?
- Mortality occurs due to fluid loss, electrolyte imbalance, hypotension and 2º infections (very serious infection)
Treatments for Dry Mouth in Sjogren Syndrome - Non-Rx: - Rx:
- Non-Rx: salivary stimulation, antimicrobial mouth rinse, saliva substitutes (carboxymethylcellulose, glycerin) - Rx: muscarinic agonists - stimulate salivation (pilocarpine, cevimeline) contraindicated in patients with asthma due to bronchoconstriction SE: muscarinic SLUD
EGFR Inhibitor Toxicities: prevention and management
- Papulopustular rash - Diarrhea - Stomatitis Toxicities will be associated with where EGFR is located in the body, as we know EGFR is very prevelant in the body in the: Skin --> hence, rash GI Tract --> hence, diarrhea, stomatitis
Due to scarce recourses, risks and benefits of selecting different organ recipients must be considered prior to selecting a recipient. Who gets the transplant? (in general)
- Patients with medical conditions that have caused a vital organ to fail However: not all patients with medical conditions need a transplant - must way risk vs. benefit (ex: patient may receive a kidney transplant due to diabetes and hypertension - not all pts with diabetes and HTN need a kidney transplant) - Bot
Platelet activating factor (PAF) major actions?
- Potent bronchoconstriction - Platelet aggregation and lysis - attraction and activation of neutrophils
Goal of Therapy in AIDS patients with CD4 cell count <200 cells/mm3
- Prevent a further decline of CD4 cells and to get them out of that window where they are at high risk for opportunistic infections - OIs are what increases mortality in patients
CENTRAL TOLERANCE: What is the AIRE? (Autoimmune regulator) What happens when there is a defect in one's AIRE?
- Protein that in humans is encoded by the AIRE gene --> a transcription factor expressed in the medulla (inner part) of the thymus that is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease ---> causes transcription of genes that usually produce proteins in the periphery causing the T-cell to be deleted - Defective AIRE contributes to autoimmune disease
Type A Blood: - RBC Antigens: - Plasma Antibodies: - Receive from: - Donate to:
- RBC Antigens: antigen A - Plasma Antibodies: anti-B antibodies - Receive from: Type A, Type O - Donate to: Type A, Type AB
Type AB Blood: - RBC Antigens: - Plasma Antibodies: - Receive from: - Donate to:
- RBC Antigens: antigen A, antigen B - Plasma Antibodies: none - Receive from: All - Donate to: AB only (has both A and B antigens therefore Type A (with anti-B), Type B (with anti-A) and Type O (with anti-A and anti-B) would all mount immune responses
Type B Blood: - RBC Antigens: - Plasma Antibodies: - Receive from: - Donate to:
- RBC Antigens: antigen B - Plasma Antibodies: anti-A antibodies - Receive from: Type B, Type O - Donate to: Type B, Type AB
Type O Blood: - RBC Antigens: - Plasma Antibodies: - Receive from: - Donate to:
- RBC Antigens: none - Plasma Antibodies: anti-A, anti-B - Receive from: Type O only (has anti-A and anti-B antibodies therefore can only receive from blood type w/o antigens to be recognized) - type O - Donate to: All (no antigens to be recognized)
The clinical presentation of a Type II reaction depends on on the type of cell that is being destroyed (by antibody-mediated complement/NK cell destruction): what would you expect if the following cells were being destroyed by the rxn: - RBC: - WBC: - Platelet:
- RBC: hemolytic anemia: fatigue, SOB - WBC: agranulocytosis: increased risk for serious infection - Platelet: thrombocytopenia: increased risk for bleeding
Innate Immune System: - Speed: - Specificity: - Cells: - Activation of adaptive immune system via: - Cells common to both:
- Speed: Rapid - Specificity: Non-specific inflammatory responses in response to antigens - Cells: Dendritic Cells Macrophages Mast Cells Neutrophils Basophils Eosinophils Activation of adaptive immune system via: - The release of cytokines - Interacting directly with cells of the adaptive immune system Cells common to both: lymphocytes without any antigen specificity - NK cells, γδT-cells (gamma-delta T cells)
Adaptive Immune System: - Speed: - Specificity: - Cells: - Clonal Selection - Cells common to both:
- Speed: slow response (at least initially w/o memory) - Specificity: specific - selection of specific WBCs with the appropriate specific antigen receptors (BCRs, TCRs) - Cells: B-cells, T-cells Clonal Selection: Antigen receptors are genetically rearranged to clonal receptors that bind to antigens displayed in MHC Complex molecules on APCs - Cells common to both: lymphocytes without any antigen specificity - NK cells, γδT-cells (gamma-delta T cells) - some effector function
Grade 3 (Severe) Infusion-related Reaction - Symptoms - Management
- Symptoms: involves more than 1 organ system, moderate symptoms (angioedema, hives, dyspnea) PLUS significant hypotension and/or oxygen desaturation! - Management: - Permanently discontinue infusion or re-challenge with a desensitization protocol (only if there is one) ADD: additional antihistamine therapy: H-1 - diphenhydramine 25 mg IV once H-2 Famotidine 20 mg IV once CCS: Hydrocortisone 100 mg IV once) Bronchodilator (albuterol) if dyspnea is occurring - Epinephrine 0.3 mg IM/SQ - Oxygen supplementation
Grade 1 (mild) Infusion-related Reaction - Symptoms - Management
- Symptoms: limited to skin or a single organ system (flushing, itching, nausea, agitation) - Management: temporarily hold infusion to prevent the infusion-related reaction from worsening ADD: additional antihistamine therapy: H-1 - diphenhydramine 25 mg IV once H-2 Famotidine 20 mg IV once ADD: CCS: Hydrocortisone 100 mg IV once) when symptoms resolve, consider restarting mAb infusion at a slower rate
Delta 32 mutation: - What is it? - How does it work?
- This mutation is present in <2% of American and Western Europeans - What does it do? Causes less expression of CCR5 receptor on the membranes of your immune (CD4) cells (the CCR5 receptor as you should remember is needed for HIV to bind to CD4 cells) Less expression of CCR5 receptor --> less CD4 infectivity with HIV because HIV Cannot find it! - Long-Term Non Progressors: Hence, Delta-32 mutation patients essentially have HIV circulating in their blood but it is essentially just "bouncing" off of their CD4 cells --> LTNPs!!!! Still have HIV but they are not infecting their CD4 cells, their CD4 cells are not being diminished because you don't have all this HIV going out and killing them off
2 similarities between autoimmune diseases and hypersensitivity reactions?
- Tissue damage mediated by T cells and B cells - Tissue damage by Type II and Type III mechanisms (cytotoxic NK/complement or Antibody-drug complex)
Treatment of antiphospholipid syndrome during pregnancy - Women with recurrent thromboses OR previous adverse pregnancy outcomes - Women with no Hx of thromboses:
- Women with recurrent thromboses OR previous adverse pregnancy outcomes - LMW Heparin - Baby Aspirin 81 mg QD (ASA) - Women with no Hx of thromboses: - Baby Aspirin 81 mg QD (ASA)
What patients will require more immunosuppressive regimens due to having an increased risk of transplant rejection?
- Younger age - African American - Poor medication adherence - Prior organ transplant - History of organ rejection - Antibodies against donor
Place in therapy for Sipuleucel-T
- asymptomatic metastatic prostate cancer - must first fail androgen-deprivation therapy
- Activation of Cytokines - Direct Cytotoxicity - Secretion of antibodies by mature plasma cells - Activation of the complement cascade all result in? (relevant to transplant)_
- cell death and graft injury - Acute cellular rejection: mediated by T-cells - Antibody mediated rejection: mediated by B cells
Fab region
- contains Fv (binds to tumor marker) - is the manufactured variation between monoclonal antibodies that is directed at the respective tumor marker
2 ways to manage hypotensive effects of anaphylaxis?
- epinephrine - IV fluids
Fc region
- identical to human IgG - coordinates with own immune system (effector cells, complement)
Why does tissue injury occur in autoimmune disease
- immunologic reaction of an organism against its own tissues due to breakdown of one or more basic mechanisms regulating immune tolerance
Immunotherapy Treatment Goal:
- induce "autoimmunity" against cancer cells - Liberate innate immune responses that are already in place, we just have to make the cancer cell recognizable again by the host's innate immune system
Platelet activating factor (PAF) is a substance released by many types of cells --> name 3
- mast cells - neutrophils - platelets
B cell functions
- mature into plasma cells which secrete antibodies specific for an antigen - can activate the complement cascade to induce complement-mediated apoptosis
What 2 factors cause pyrexia? (HIV can block this process)
1. Pyrogens released by organisms (pathogens) 2. Cytokines released in response to such pyrogens that allow for rise in temperature set point - HIV blocks release of cytokines, hindering immune system's ability to mount temperature response
Stem-cell transplants that have been used in clinical trials (Berlin Patient, Boston Patient LTNP)---> efficacy in average HIV positive patient?
- only 2 of them have been successful enough to prove a "functional cure" (Both had the ∆32 CCR5 mutation and comorbid cancer diagnoses) - the stem cell transplant is very specific to the Delta-32 CCR5 mutation that decreases the CCR5 expression on the cell surface (CD4) causing less HIV infectivity to the T-cells in general. - candidates without a comorbid cancer diagnoses and without the ∆32 CCR5 mutation as of now are not candidates for stem cell transplant - no data to support
Pharmacist's Role in immunotherapy
- prescriber education on new therapies and their place in practice - role of cost in choosing therapies (patient assistant programs, formulary management) - safety (REMS programs, toxicity monitoring and treatment)
Common Allergens
- β-lactam antibiotics (penicillins, cephalosporins) - Sulfonamides - NSAIDs - Biologics (minor-full on anaphylactic, normally murine/chimeric) - Excipients - Latex
What are the 2 primary roles of the immune system?
-Protects patients from invasion by infectious pathogens -Distinguishes self from non-self
3 signals of T-cell activation
1. Recognition: T-cell Recognition of Antigen via presentation by APC on MHC 2. Costimulation 3. Proliferation
Patient related factors to consider in Cancer Immunotherapy
1. Aggressiveness of tumor (indolent/less aggressive) - pick fast acting vs. delayed acting therapy (checkpoint) 2. Performance status - can they tolerate toxicities 3. Autoimmune conditions - will they be exacerbated by medication 4. Immunosuppression 5. Financial Status 6. REMS Program 7. Treatment expectations/immune response - ensure we have clear tx expectations - we know the timeline to expect and immune response 8. Ability of patient to adhere to treatment and report/seek help if toxicity were to occur
What are the 2 elements of the humoral immune response?
1. Antibody production by B-cells 2. Complement activation by antibodies -- cell death of transplant
Steps of Antibody Drug Conjugate MOA
1. Antibody recognition: antibody attaches to the antigen and/or receptor 2. Internalization: Internalization of the entire antibody-drug complex, once internalized it then combines with a lysosome: 3. Release of cytotoxic agent: A lysosome then can allow for the proteolytic degradation of the linker to release the cytotoxic agent that will kill the tumor cell into the cell 4. Microtubule or DNA Disruption: cytotoxic agents then can leave the lysosome and exert their activity at the microtubule level (DM-1 or MMAE) or DNA level (Calicheamicin)
Treatment of DRY EYES in Sjogren Syndrome (3 options
1. Artificial tears RX: 2. Restasis: cyclosporine eye drops 3. Lifitegrast eye drops (Xiidra)
How are Antibodies produced? (5 steps)
1. B-cell recognized antigen via BCR which results in B-cell activation 2. B-cell engulfs antigen and breaks it up into fragments 3. B-cell displays antigen fragments on MHC which attracts helper T-cells, which recognize the antigen presented on the B-cell surface and begin to produce cytokines as a result 4. As a response to cytokine release, B-cells begin to proliferate/multiply 5. B-cells mature into antibody-producing plasma cells --> secrete antibodies
What are the 4 primary factors that determine Transplant Compatibility
1. Blood Type Compatibility (ABO Types) 2. HLA Compatibility (Class I, Class II) 3. Sensitization 4. Other factors depending on organ type (donor size, recipient anatomy)
What are the 4 bodily fluids of HIV transmission
1. Blood: Sexual, injectable (needle transmission) or perinatal transmission, transfusions 2. Semen: Sexual encounter 3. Vaginal secretions Sexual encounter Breast milk Perinatal transmission
What defines severity of disease? (HIV)
1. CD4 COUNT: dictates whether or not a patient has AIDS (<200 cells/mm3) 2. Check Viral Load: NAT or HIV RNA Test 3. Clinical Symptoms - < 200cells/mm3: constitutional signs and symptoms, opportunistic infections, potentially death
Immunocompromised patients will be susceptible to many infections that would normally not occur in immunocompetent patients, give 4 examples:
1. Common Cold 2. Toxoplasmosis 3. Pneumonia 4. Thrust
Toxicities with CAR-T cell Therapy
1. Cytokine Release Syndrome 2. Neurotoxicity 3. Hypogammaglobulinemia (low IgG) - delayed toxicity
Black Box Warnings of Blinotumomab
1. Cytokine release syndrome -> related to peak cytokine levels, typically occurs within 2 days of initiation or dose escalation --> fever, headache, nausea, hypotension, increased LFTs 2. Neurological toxicities: unclear etiology, avg onset 7 days --> encephalopathy, seizures, confusion, altered consciousness, speech and balance changes (Tremor)
4 potential mechanisms for HIV vaccine development
1. DNA: HIV genes injected into DNA and thereafter injected into a patient to develop memory cells - not currently available 2. Live Vectors:(furthest along in development for HIV vaccine) HIV genes incorporated into viral or bacterial vectors for immune system to develop memory cells 3. Viral proteins/peptides: Pieces of HIV proteins- enough to produce B and T cell response 4. Virus-like particles: Include HIV shell without anything in it to prevent replication but to stimulate immune response due to glycoprotein introduction
mAbs exert their immunotherapy activity in a 2 step process, the first step is Antibody Recognition: the antibody recognizes the tumor or (antigen of the APC). The second step is exertion of the antibody effect which can occur by 4 mechanisms. Some mAbs can use multiple mechanisms. What are the 4 mechanism by which mAbs can exert their activity?
1. Direct Apoptosis or Growth Inhibition 2. Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): 3. Complement-dependent Cytotoxicity 4. Block Neovascularization (VEGF Inhibitors)
How to Prevent Blinatumomab Toxicity (4 methods)
1. Dose escalation in first cycle - therefore risk of cytokine release is the highest- start patient at lower dose for first 1-7 days until some of the tumor is allow to die off then increase the dose - gives you the ability to mitigate how many cytokines are released all at once 2. Overfill bags to prevent breaks in therapy: if that happens we have now stopped the infusion, and when we restart the infusion we would again put the patient at risk for cytokine release syndrome because we are re-initiating therapy --> AVOID ANY STOPS IN THE INFUSION!!! - hence, we put overfill in the bag 3. Steroid Premedication (re-initiate if there are any breaks in therapy) 4. No flushing of the infusion line! -- would cause a pretty significant volume of Blinatumomab being given all at once (even if it is just the residual drug lef tat hte end of the infusion IV line) and if we give Blinatumomab at too quick of a rate we might cause cytokine release syndrome so we really work with our nursing colleagues to not flush the line so that we do not give Blinatumomab too quickly, even the amount that's in the line.
5 environmental factors that can cause autoimmune disease
1. Drugs ex: Lupus autoantibodies. autoimmune hemolytic anemia 2. Ultraviolet light - Locally stimulates release of cytokines and formation of antibodies - May interfere with activation of macrophages - May increase generation of autoreactive T cells 3. Cigarette smoke 4. Silica dust 5. Infections ex: - Epstein-Barr virus may be a triggering event - Trypsomoniasis and mycobacterial infections may induce anti-DNA antibodies or lupus-like symptoms
There are 2 types of autoimmunity mechanisms what are they
1. Exogenous: molecular mimicry 2. Endogenous: altered antigen presentation, apoptotic defects, cytokine imbalance, altered immunoregulation
Signal 3: Proliferation of T-cells
1. Following activation of T-cells by co-stimulatory binding between APC and T-cell CD receptors: T-cells are activated and release cytokines such as Interleukin-2 which activate pathways to trigger cell proliferation (which is important because it leads to nucleotide synthesis - by activating the cell cycle it allows for the production of large # of effector T-cells which can lead to further transplant rejection) 2. Lymphocyte proliferation requires nucleotide synthesis 3. In the end- a large number of effector T-cells are produced - further rejection
Steps of HIV infection of a host cell (natural progression of infection when HIV-infected patients are not on any medication at all)
1. Fusion of HIV to the host cell surface using glycoproteins and CD4 receptors (CXCR4) 2. HIV capsid is unloaded into the host cell: HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell 3. HIV uses the host cell enzymes in order to replicate itself: (steps 3, 4, 5) - Viral DNA is formed by reverse transcription of HIV RNA (reverse transcriptase) - Viral DNA is transported across the nucleus and integrates into the host DNA (integrase) - New viral DNA is used as genomic RNA and to make viral proteins 4. Once it uses the host cell machinery for its own replication cycle: the host cell dies CD4 cells are dying Monocytes are dying --> immune cells being killed off as HIV replicates 5. HIV replicates itself and buds out mature new virions for HIV to go out and infect new CD4 cells and new monocytes - New viral RNA and proteins move to the cell surface and a new, immature, HIV forms 6. The virus matures by protease releasing individual HIV proteins --> mature virion ready to infect new immune cells
3 primary etiologies of autoimmune disease
1. Genetics 2. Environmental Factors 3. Hormones
3 Treatment Modalities of GBS
1. IVIG (intravenous immunoglobulin) 2. Plasma exchange: essentially to remove the antibodies that are causing the problem (Removes harmful antibodies & replaces plasma with substitute) 3. Supportive Care: - Monitoring blood pressure/respiratory function - Prevention of blood clots - Physical therapy and psychosocial support
The most important first step when evaluating immune-related adverse events (due to checkpoint inhibitor therapy) is to rule out other etiologies. What are 4 possible etiologies of immune-mediated adverse events (rash/dermatitis/colitis/hepatitis/pneumonitis)
1. Infection 2. Medications 3. Metabolic 4. Neoplasm - anything related to the cancer itself
2 Mechanisms of altered antigen presentation
1. Loss of immunologic privilege 2. Protein alteration: changes of proteins in the body due to inflammation, drug exposure and normal cell aging which can generate immune responses thereafter
After about 10 days following exposure, during the acute stage of infection, HIV Viral Load will reach a high spike. During this time CD8 cytotoxic T-cells play a crucial role in stabilizing the viral load (prevent it from further increasing), how do they do this? Note: stabilization is normally seen around 30 days after infection
1. Lyse infected cells 2. Cell lysis causes release of interferon gamma (cytokine) to facilitate inhibition of further viral replication 3. Bind to CCR5 chemokine receptor to prevent the binding of HIV: Prevents binding of CD4 cells/Monocytes to HIV--> prevents the infection of HIV to those cells HOWEVER - MUTATIONS CAN OCCUR WITHIN THE HIV that allow them to hide from CD8 cells
For what high-risk populations does the CDC recommend Annual HIV testing?
1. MSM (men who have sex with men) 2. Sex with an HIV+ partner 3. More than 1 partner since last HIV test 4. IV-Drug abuse/shared needles 5. Sex workers 6. History of STDs, hepatitis, Tuberculosis
Two places where the cytotoxic agent of antibody-drug conjugates can exert activity? Examples of cytotoxic agents that participate in each mechanism?
1. Microtubule Level: prevents the microtubule from polymerizing or growing; or promotes the microtubule to degrade or shorten. Essentially suppressing the microtubule action in the cell DM-1 and MMAE 2. DNA Disruption: goes to the DNA and exerts cytotoxic effects Calicheamicin
What are the 3 forms of central tolerance
1. Negative Selection 2. Transcription of proteins that initiation T-cell deletion in the periphery triggered by AIRE 3. Receptor Editing
What factors must you consider before selecting a patient-specific immunosuppression maintenance regimen
1. PT specific risk factors (organ type, infection history, malignancy hx, age, race, adherence, prior transplant, hx of rejection, antibodies against donor) 2. How well they tolerate these medications based on agent-related side effects (nephrotoxicity, bone marrow suppression, poor wound healing, hyperglycemia, neurotoxicity)
How do patients develop antibodies to donors (3 risk factors for a positive crossmatch)
1. Pregnancy 2. Blood transfusions 3. Prior transplant
Diagnostic test that detects IgG antibodies only suing Western Blot and Immunofluorescent Assay
1st Generation Test: used to be used, had a lot of cross-reactivity with other contaminants and a lot of false positive
2 primary advantages of using a combination of immunosuppressive agents in preventing rejection?
1. Reduce risk of rejection: prevent multiple steps in T-cell signaling (select agents that each target a different signal in T-cell response) 2. Limit Toxicities: combination allows for the use of lower doses of multiple drugs instead of higher doses of one drug - limits ADRs
Complications after Transplant: what 2 main factors must you balance to manage complications after transplant?
1. Rejection: minimize rejection with maintenance agents which also increases risk of toxicity/malignancy/infection 2.Toxicity/Infection/Malignancy: too little immunosuppression minimizes risk for toxicity/infection/malignancy but increases risk of transplant rejection
3 potential fates of a recipient that is a positive crossmatch for a viable donor?
1. Remain on the waitlist for the next organ donor 2. Desensitization: giving very high and intense doses of immune suppression to try and overcome that reaction that is occurring 3. Paired kidney exchange: two different organ pairs can donate to opposite recipients in the case where there would be no reaction
5 examples of disease states due to molecular mimicry (exogenous autoimmunity)
1. Rheumatic Fever: streptococcal cell wall antigen stimulates an antibody response, and some of these antibodies thereafter can cross-react with the proteins in heart tissue causing rheumatic fever 2. Lyme Disease 3. Type 1 Diabetes 4. Rheumatoid Arthritis 5. Multiple Sclerosis (MS)
3 types of Type III reactions
1. Serum sickness 2. Serum sickness-like disease 3. Drug-induced vasculitis
What are the 4 most common modes of transfer of HIV?
1. Sexual: blood, semen, vaginal secretions 2. Injectables: blood: individuals who are using injectable drugs, illicit or not illicit: sharing needles with a person that is HIV positive --> blood transmission can carry the infected-HIV and infection another human 3. Perinatal (Mother-> Child during pregnancy through umbilical cord, during labor as high level of blood is exchanged from mother to child, after labor in breast milk) 4. Transfusions: blood (prior to 1985 transfusions were given without checking for HIV - hence spread)
2 types of induction agents
1. T-cell Depleting: Alemtuzumab, Antithymocyte globulin 2. Non T-cell Depleting: Basiliximab
Checkpoint Inhibitors MOA
1. Tumor cell primes an APC when the APC is exposed to it 2. T cell then comes along to interact with this APC. On the T cell there are two key markers: CTLA4 marker and CD28 marker. On the APC there are B7 Markers which can interact with both the CTLA4 or CD28 marker 3. B7 of APC + CD28 of T cell: When the B7 markers ---> CD28 marker of T-cell: this activates the T cell against the tumor cell, ultimately resulting in Tumor Cell kill (tumor cell is killed by the T cell) 4. B7 of APC + CTLA4 of T cell: inactivates the T cell, essentially stopping the T cell from killing the tumor cell. The tumor cell is then able to go unnoticed, and is allowed to survive because the T cell no longer kills it because it is inactive 5. Ipilimumab: a checkpoint inhibitor that targets CTLA4, when it blocks CTLA4 it shunts all of the B7s on the APC to instead bind to CD28 on T cells(B7 can't bind to CTLA4 when it is blocked by Ipilimumab therefore it will bind to CD28 instead), this stops the T cell inactivation and allows for the activation of T cells --> allows for the tumor cell kill to happen again 6. If PD-L1 is upregulated by the tumor this allows for a lot of interaction with the PD-1, and ultimately when they interact this inactivates the T-cell! This is the mechanism by which tumor cells learn to survive, by upregulating PD-L1 so that they inactivate all of these T cells! - evade immune ---> tumor cell kill process stops, tumor cell goes unnoticed and it is not killed by the T cell 7. Drugs that inhibit this PD-1 + PD-L1 interaction: PD-1 Inhibitors (on T cell): Atezolizumab, Avelumab, Durvalumab PD-L1 Inhibitors: Nivolumab, Pembrolizumab, Cemiplimab All of these drugs are similar to ipilimumab (CTLA4 inhibitor) in that they stop the inactivation of T cells, and allow for the activation of T cells to ultimately result in Tumor Cell kill again
Important pharmacy-patient counseling points when dispensing and in-home HIV test
1. What their risk factors are 2. How to minimize their risk factors for HIV transmission 3. A contingency plan on what happens if they are HIV positive: Where do they go, How do you link them into care, How do you counsel them on what it means to be HIV positive
2 categories of autoimmune disease
1. organ-specific 2. systemic ***autoimmune diseases may overlap, some immunotherapies can induce autoimmune diseases, especially in a pt that already has an active uncontrolled autoimmune disease**
Molecular mimicry
Confusion between foreign microbial product and a self-antigen that ultimately leads to activation of autoreactive lymphocytes (self-targeting lymphocytes)
There is no diagnostic test for HIV that will be able to diagnose a patient the day after they have been exposed. You must wait at least_____________days to be able to diagnose patients with HIV after their exposure
10-14 days (HIV viral load =10 days, 14-15 days = p24 antigen)
when does seroconversion typically occur?
2-8 weeks (on average 25 days)
Diagnostic Test: Detection of IgG antibodies without cross-reactivity with other contaminants (cellular proteins)
2nd generation test
All HIV RNA gets replaced within?
3 days
Most toxicities of both cytokine therapies (interleukin and interferon) resolve with _______ after holding the medication
3-6 days
Acute anaphylaxis onset
30 min-2 hours after administration of a drug (almost never beyond, but can be) -- mins-hours
When should pre-medications be given to prevent infusion related reactions due to mAb immunotherapy?
30-60 minutes prior to infusion - Antihistamine: Diphenhydramine 25 mg IV/PO +/- Acetaminophen 650 mg PO +/- Corticosteroids: hydrocortisone 50 mg IV +/- Montelukast 10 mg PO
Diagnostic Test: Detection of IgG and IgM antibodies
3RD GENERATION
Diagnostic test: Detection of IgG, IgM and p24 antigens, results specify positive or negative but do not specify which marker is positive
4TH GENERATION (preferred)
1st line diagnostic test
4th and 5th generation: - Detect: - IgG, IgM (early as 25 days) and p24 antigens (15 days) - 4th gen: doesn't specify which value is positive, just tells you + or - - 5th gen: same markers but specifies exactly which marker was positive
Diagnostic test: Detection of IgG, IgM and p24 antigens and specifies which marker is positive
5TH GENERATION (preferred)
When will a positive HIV RNA (viral load) test become detectable?
After ~ 10 days post-initial infection - measures # of copies of HIV/1mL of blood
- CD4 cells lose the ability to replicate because of the vast amount of HIV virus they are being burdened with - CD8 cells are needed to give the body a "fighting chance" by inhibiting viral replication - Non-neutralizing antibodies are present but are not typically used from a diagnostic perspective. (neutralizing antibodies have weak neutralizing activity against primary HIV isolates and thus probably contribute very little to the initial control of HIV) What stage of HIV infection is being described?
Acute HIV Infection
HIV-1 Antibody/antigen (-) NAT (+) stage of infection?
Acute HIV-1 Infection
HIV progression despite antibody production a few weeks after infection
Adaptability of HIV's glycosylation site resulting in prevention of antibody neutralization -- --> progression evades immune response (even if antibodies are produced a few weeks after infection - infection progression is enabled)
Which immune system is more involved with organ transplant rejection, why?
Adaptive immune system: T-cells and B-cells are the cells that are responsible for causing rejection of the transplanted organ
OraQuick In-Home HIV Test is an in-home oral swab that produces results within 20-40 minutes. Sensitivity: 92%, Specificity: 99.98% Advantage: Disadvantage:
Advantage: get benefit of getting results right at home - encourages more patients to get tested Disadvantage: The sensitivity is low (92%), less reliable so you would ABSOLUTELY NEED a confirmatory test --> gives info on what to do if it is positive - requires counseling: if you are dispensing these tests or have a pt that gets identified as being positive using one of these tests, there are clearly risk factors that the patient will believe they have it (even if it may be a false-positive) --> much pt education needed
Definition of hypersensitivity reaction
Adverse drug effects that involve immunologic mechanisms: an overly enthusiastic response of the immune system to a drug, that eventually leads to tissue damage (local: rash, SOB-tissue damage in lungs)
Sequence of appearance of laboratory markers for HIV-1 Infection (which tests would appear positive at these time markers) After > 10 Days: 15 days: 25 Days: ~38 days: (IgM and IgG) 50 days:
After > 10 Days: NAT/HIV RNA Test for viral load = positive (false positives common - need confirmatory Ab test) Cannot be used alone for diagnostic purposes 15 days: p24 antigen test positive --> 4th or 5th generation Ag/Ab Test Any 4th or 5th gen immunoassays (Ag/Ab tests) A little after 2 weeks after exposure 25 Days: 3rd generation antibody IgG and IgM Antibody test Earliest detection date with Ab tests (ab-only) = 25 days, hard to wait that 25 days to be able to diagnose a pt because in those 25 days the patient could have been infecting other individuals during that time period (~38 days): 2nd gen antibody - IgG w/o cross-reactivity 50 days: 1st gen Antibody-test (IgG only)
How is Trastuzumab a special case of an antibody-drug conjugate?
Along with its cytotoxic component it also retains activity --> ADCC--> recruits NK T-cells to induce cell lysis
Plasmapheresis IVIG (intravenous immune globulin) Anti B-cell Agents are all treatments for
Antibody-mediated rejection (b-cells)
Immunosuppressive Agentor Anti-rejection Medication definition
Any medication used to suppress the immune system in order to prevent or treat rejection
NK cells function in defense against HIV
Apart of innate immune response --> - serve to lyse cells with a decreased MHC 1 complex that are expressed on the infected cells (decreased MHC = identification mechanism) --> this stimulates cytokine release which then inhibits viral replication
NSAID that most commonly reported with an associated allergy
Aspirin: most commonly respiratory and skin rxns (desensitization may be required if a pt needs aspirin for secondary prevention of a cardiovascular event)
Antiphospholipid Syndrome
Autoantibodies that result in increased coagulation activity - Antiphospholipid antibodies attack blood proteins involved in homeostasis --> procoagulant syndrome results --> thrombosis
Celiac's Disease mechanism
Autoimmune diesease charcterized by immune reaction induced by proteins that are derived from gluten (gliadins and glutenins) --> upon exposure to these proteins, tissue trans-glutaminase causes a deamidation of glutamine residues in gluten to form glutamic acid - Glutamic acid is then recognized by APCs as foreign --> activation of T cells occurs --> secretion of immunomodulators that destroy enterocytes of the GI villous atrophy
How is gender a risk factor for autoimmune disease
Autoimmune disease generally occurs in women>men --> this can be explained by the effect of sex hormones on gene expression --> the presence of the disease and disease severity does seem to increase during and after pregnancy
non-depleting, chimeric (human/ murine) monoclonal antibody directed against the IL-2 receptor cluster of differentiation 25 (CD25).5 It inhibits T-cell proliferation and differentiation, but does not cause T-cell depletion.
Basilixumab
What 3-drug regimen is Belatacept (signal 2 co-stimulation inhibitor) commonly used in for maintenance immunosuppression?
Belatacept (sig 2) + Antimetabolite (sig3) +/-Prednisone (antimetabolite = AZA or mycophenolate)
How can antibodies Block Neovascularization (specifically VEGF inhibiting mAbs)
Bind up all of the VEGF in circulation, preventing angiogenesis from occurring, preventing the flow of blood, nutrients and all of the necessary things that the tumor cell needs in order to grow VEGF Function: helps promote the angiogenesis, and blood flow to the tumor cell to promote tumor cell growth
What class of drug is Blinatumomab?
Bispecific T-cell Engager (BiTE)
blood type transplant compatibility chart
Blood Type Compatibility - DA --> RA - DA --> RAB - DB --> RB - DB-->RAB - DAB --> RAB - DO --> RA, RB, RAB, RO
One of the 1st key factors to confirm in determining a donor and recipients compatibility?
Blood Type Match: - DA --> RA - DA --> RAB - DB --> RB - DB-->RAB - DAB --> RAB - DO --> RA, RB, RAB, RO
How dependent is transplant rejection on HLA matching vs. Blood type matching
Blood type matching: must be a viable match to prevent hyper-acute rejection HLA Compatibility: compared to blood typing where we need to make certain that they match, recipient's HLA do not need to be perfectly matched to their donor's HLA-- That is largely due to the different HLA rejection medications we have available today
very common target in lymphoma and leukemia population
CD20
What is the MAINSTAY of treatment of immune-mediated adverse reactions (to checkpoint inhibitors)
CORTICOSTEROIDS (if refractory to CCS, infliximab may be indicated)
Ipilimumab is a checkpoint inhibitor that inhibits
CTLA-4 on the T-cell surface which interacts with B7 on an APC to inactivate the T-cell. By inhibiting this it further permits T-cell activation and Tumor cell lysis
Maintenance agents that target Signal 1 of T-cell Response (recipient T-cells recognize donor antigens that are presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells)
Calcineurin Inhibitors: - Cyclosporine - Tacrolimus
Define Central tolerance in terms of negative selection?
Cell death is induced in autoreactive T-cells in the thymus (T-cells towards self-antigens) (apoptosis of self-reactive lymphocytes)
Antigen Presenting Cells
Cells that digest antigens, present it on their membranes for recognition by T cells bearing receptors for that antigen (ex: dendritic cells)
Steroids (methylprednisolone) and Anti-thymocyte globulin are treatment for
Cellular rejection (T-cell mediated)
Neutralizing antibodies are present: antibodies towards some of the HIV glycoproteins (gp120, gp41 - HIV) as well as some of the receptors (CXCR4 - C4 T-cells/CCR5 - Monocytes) What stage of HIV infection is being described?
Chronic HIV Infection (antibodies have been made)
A group of plasma proteins that enhance phagocytosis, cell lysis and activation of mast cells
Complement: a system of about 30 different plasma proteins involved in several different immunologic functions
Class I HLA molecules (MHC present on all nucleated cells) can be recognized by _________ T-cells, whereas Class II HLA molecules (present on APCs with immune function: dendritic, macrophages, B-cells) can be recognized by __________ T-cells.
Class I --> CD8 Cytotoxic T cells Class II --> CD4 Helper T-cells
What are the 2 classes of HLA proteins? What are the types of each of them? Which alleles are of most concern for transplant matching?
Class I and Class II - Class I: HLA-A, HLA-B, HLA-C - Class II: HLA-DR, HLA-DQ, HLA-DP Biggest concern: Class I hla-A, Class I hla-B, Class II HLA-DR (within each subtypes there are more subtypes - A1, A2, A3 . . .)
What symptoms will you see in a patient during Chronic-Phase HIV that has not yet progressed to a CD4 cell count < 200 cells/mm3?
Clinical Latency: asymptomatic--> virus continually multiplying but CD4 cells dying, hidden from CD8 cells, B-cells not being produced --> no immune response, no symptoms
Treating patients with hypogammaglobulinemia due to previous CAR-T cell therapy
Consider IVIG --> repletion of IgG antibodies with manufactured IgG to prevent infections (pts are at high risk for infections without IgG supply)
What symptoms being to arise once a patient's CD4 cell count drops below 200 cells/mm3
Constitutional signs and symptoms Opportunistic infections Potentially Death
Mechanism of Guillan-Barre Syndrome
Cross reactivity of IgG antibody between bacterial LPS and host gangliosides --> immune response causes T-cells to infiltrate CNS and PNS --> Ig binds to gangliosides and activates immune response --> damage to peripheral nerves ----> blocks signal conduction (hence weakness, tingling in the legs that may spread up to arms and face)
If ampicillin causes a hypersensitivity reaction in a patient, amoxicillin will likely cause a hypersensitivity in the patient as well, what is this referred to as?
Cross-Antigenicity, cross-reactivity: drugs with similar structure may both cause hypersensitivity reactions in relevance to one another: if an HS happens with one, it is likely to happen with the other
Type IV reactions usually present as
Cutaneous reactions: - ex: poison ivy
BLACK BOX WARNING OF HER-2 mAbs:
Decreased left ventricular ejection fraction (heart failure): Prevention: not much we can do, but it would be something we would monitor for prior Often times these HER-2 directed mAbs are given in addition to other cardiotoxic chemotherapy agents like anthracyclines -- therefore, if so, we would at least want to separate the administration, not give them at the same cycle: Ex: give the anthracycline for a couple months, then add the Trastuzumab AFTER the anthracycline is DONE for a couple months
What cells serve as the first line of defense for HIV within one's body? Why?
Dendritic cells: - You have epidermal Dendritic Cells, therefore they live in the cervical area and rectal area, which is typically your first point of contact especially for sexual transmission of HIV - Epidermal Dendritic Cells transport the HIV to your "immune hub" aka the lymph nodes - Your immune cells live in the lymph nodes, therefore the common, initial symptoms of HIV used to be lymphadenopathy
last resort if a penicillin is the treatment of choice for an infection, the patient has a true Type I penicillin allergy and no acceptable non-penicillin antibiotics are available? How does it work?
Desensitization to the specific β-lactam required for the treatment of the infection (will reduce risk of an IgE mediated rxn such as anaphylaxis) --> protocol that works by rendering the mast cells less responsive to degranulation - because of anaphylaxis this should ONLY be performed in a hospital setting usually in a ICU with a 1:1 of patient:nurse over a period of several hours with close observation - temporary induce tolerance so that the patient can be treated with the medication (VERY TEMPORARY) lapse within as little as 24 hours can be seen
Which rapid test is tests for HIV-1 antibodies, HIV-2 antibodies AND p24 antigen?
Determine - finger stick - 99.9% sensitivity (+ = +)
HER-2 Inhibitor Toxicities: prevention and management
Diarrhea Rash Decreased LVEF (must separate administration from anthracyclines) black box warning HER-2 is actually related to EGFR and is similarly expressed in the epithelial cells of our skin and GI tract (hence diarrhea and rash)
If a patient gets a rapid antibody or lab test done and it comes back positive, what must be done thereafter despite high test sensitivity (positive=positive)
Do another test to confirm. the result - always want to get 2 confirmatory tests for patients especially if positive
Azathiopurine Drug Class Indication: MOA: Dosage Forms: ElimiNATION: urinary Adverse Effects (2):
Drug Class: Antimetabolite Indication: Maintenance (Signal 3) - proliferation MOA: Active metabolite resembles nucleotides and is incorporated in the growing DNA strand to halt the cell cycle Dosage Forms: Tablets and oral suspension ElimiNATION: urinary ("urination") Adverse Effects (2): - Bone marrow suppression: low WBC, RBC, platelets - GI Effects: N/V, diarrhea
Mycophenolate Drug Class Indication: MOA: Dosing (conversion b/w dosage forms): Cellcept = caps, tabs, PO solution, IV Myfortic: DR tabs Adverse Effects (2): (same as AZA)
Drug Class: Antimetabolite Indication: Maintenance (signal 3-inhibition - T-cell activation) MOA: Inhibits the de novo synthesis of guanosine nucleotides that T- and B-cells rely on for DNA synthesis, stopping cell proliferation Dosing (conversion b/w dosage forms): Cellcept 1000 mg = Myfortic 720 mg Adverse Effects (2): - Bone marrow suppression: low WBC, RBC, platelets - GI Effects: N/V, diarrhea
Cyclosporine Drug Class: Indication: MOA: Typical Trough levels: Dosing Limitations: eLimination: Adverse Effects (2):
Drug Class: Calcineurin Inhibitor Indication: Maintenance (Signal 1 Inhibition) MOA: Inhibition of production and release of interleukin II via complexation with calcineurin in T-cell signaling pathway therefore inhibition of IL-2 induced activation of resting T-cells Typical Trough levels: 100-300 mg/dL Dosing Limitations: Sandimmune: IV, cap, oral solution Neoral, Gengraf: caps, oral solution PATIENTS MUST REMAIN ON THE SAME DRUG FORM - MUST MAINTAIN TROUGH LEVELS - DOSAGE FORMS NOT INTERCHANGEABLE must use trough levels to determine how immunosuppressed the patient is immunosuppression eLimination: biliary (hepatocytes -> bile -> renal tubular secretion) Adverse Effects (2): - nephrotoxicity - neurotoxicity counsel the pt on the importance of going to all their scheduled appointments so that they are being monitored appropriately in terms of blood levels so we know that they are not at risk of getting toxicity
Tacrolimus Drug Class: Indication: MOA: Typical Trough levels: Dosing Limitations: eLimination: Adverse Effects (2): (same as Cyclosporine)
Drug Class: Calcineurin inhibitor Indication: Maintenance (Signal 1) MOA: Suppresses cellular immunity (inhibits T-lymphocyte activation), by binding to an intracellular protein, FKBP-12 and complexes with calcineurin dependent proteins to inhibit calcineurin phosphatase activity Typical Trough levels: 5-15 mg/dL Dosing Limitations: Goal levels depend on organ time, time since transplant, other clinical factors •Prograf: capsules, IV solution •Astagraf: capsules (extended release) •Envarsus: tablets (extended release) - dosage forms not interchangeable eLimination: biliary Adverse Effects (2): nephrotoxicity, neurotoxicity
Lifitegrast eye drops (Xiidra) - Drug Class: - Pt Counseling: - SE:
Drug Class: Lymphocyte function-associated antigen-1 (LFA-1) antagonist Counseling: Remove contact lenses prior to use SE: Taste changes, blurred vision, irritation, headache Rx eye drops used to treat dry eyes due to Sjogren syndrome
Basiliximab Drug Class: MOA: Dosing: Indication: Adverse Effects:
Drug Class: Non T-cell depleting induction agent, CD52 mAb MOA: Binds to and blocks the α-chain of the IL-2 receptor (CD25), specifically on the surface of activated T-cells (the cell cycle has already occurred) which blocks signal 3 of T-cell response --> T-cells have already been activated, and are ready to mount a response to the donor organ (further initiated by IL-2) and proliferate but Basiliximab prevents this: only works on activated T-cells, is not actually inhibiting any T-cells from being activated from Signal 1 and Signal 2 therefore is MUCH LESS POTENT! (hence, non t-cell depleting) Dosing: 2 Doses, one before perfusion and one a few days later post-transplant Indication: Induction - better tolerant, less potent Adverse Effects: well tolerated
Alemtuzumab Drug Class: MOA: Dose: Indication: Adverse Effects: (2) Conditions given under:
Drug Class: T- and B-cell depleting agent, Anti-CD52 mAb, most potent induction agent MOA: Targets CD52 on T-cells, B-cells, macrophages, monocytes, and natural killer cells to cause lysis and cell death Dose: 1 time dose Indication: Induction (intense immunosuppression to prevent immediate rejection) Adverse Effects: - Bone marrow suppression: low WBCs, platelets, neutropenia - Infusion reactions: cytokine release syndrome, serum sickness (Type III to antisera) Conditions given under: Controlled setting, patient is under anesthesia, ppl are watching --> the AE are able to be more controlled
Antithymocyte Globulin Drug Class: MOA: Dosing Limitations: Indication: Adverse Effects: (2)
Drug Class: T-cell depleting agent MOA: Targets CD2, 3, 4, 8, 11a, 18, 25, 44, 45 on T-cells and dendritic cells to cause lysis and cell death Dosing Limitations: because its given 3-4 doses, it is not being given in the OR (under anesthesia in a controlled setting), so patients are at a much higher risk for developing the infusion reactions Indication: Induction Adverse Effects: (2) - Bone marrow suppression: low WBCs, platelets, neutropenia - Infusion reactions: cytokine release syndrome, serum sickness (Type III to proteins from non-human source)
Celiac's disease relevance in pharmacy
Drug excipients may contain gluten: look at package insert info on excipients for "starch" -- problem/trigger for Celiac's patients
A febrile response that coincides with administration of a drug and ceases when the drug is discontinued --- without other symptoms of systemic illness/infection
Drug fever
Purplish lesions on the skin are a typical clinical presentation of?
Drug-induced vasculitis (Type III)
Symptoms of Sjogren Syndrome
Dry Glands/Ducts: autoantibodies target muscarinic receptors in salivary and mammary glands (most commonly dry eyes, dry mouth)
Which perinatal stage is a baby most at risk for transmission of HIV from the mother?
During labor: highest level of blood exchanged from the mother to the child during this time
Why is it a significant factor to notice that mTOR inhibitors cause poor wound healing?
Emphasizes to NOT give Sirolimus or Everolimus to patient's right after transplant surgery or if they have upcoming surgery: poor wound healing - bleed risk
What components of the HIV life cycle do current antiretroviral agents inhibit?
Entry Inhibitors: Fusion, CCR5, CXCR4: prevent the binding of HIV to the CD4 cell Reverse transcriptase inhibitors: nucleoside, non-nucleotide reverse transcriptase inhibitors that prevent the use of RT Integrase Inhibitors Protease Inhibitors
A patient comes to clinic with apparent type I reaction --> their BP is 2/10 (lmao) and they are experiencing severe SOB. What drug agent should you give them?
Epinephrine: bronchodilation (allow pt to breathe), vasoconstriction (increase BP) can also give the pt IV fluids to help increase BP
RV144
Failed AIDS HIV Vaccine study but marked the point where we were able to build more vaccines from that standpoint - Over a 3.5 year time period it was a 31% effectiveness seen within RV144: A lot of this was due to the booster that was given to patients
Fas Ligand and BCl-2 role in activation induced cell death of lymphocytes
Fas Ligand: pro-apoptotic - induce apoptosis BCL-2: anti-apoptotic proteins (mutation is a driver of cancer cell proliferation -- allows them to stay alive/resist apoptosis)
2 proteins involved in the extracellular pathway of apoptosis? (if dysregulated can lead to autoimmunity)
FasL: pro-apoptotic TNFα
Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) of mAbs
Fc region of the mAb binds to the FCR receptor on effector cells (such as NK cells), resulting in a release of inflammatory and cytotoxic proteins that ultimately results in cell death.
Where is GD2 in our body? What does this tell you about the Toxicities of GD2 inhibitors?
GD2 is expressed on our peripheral pain fibers, therefore when we use Dinatuximab which targets GD2 it will also target our peripheral pain fibers, which results in profounnnnd NEUROPATHIC PAIN for patients receiving these therapies
DH presents to the ER with a sprained ankle and you are the pharmacist doing medication reconciliation. She tells you she's allergic to sulfa drugs and Percocet. What questions should you ask to about her previous hypersensitivity reactions?
Get detailed allergy history from the patient - Drug Name/route/indication of medication (why they were taking) - Description and severity of reaction/nature of it, where was it - Temporal relationships: when did it onset after admin - Prior exposure, re-challenge or diagnostic testing (1st time? 1st dose?, skin testing in past? related meds?) - Management of reaction and response to treatment (self-limiting? epi in hospital? response?)
Goal of cytokine therapy
Give max number of doses without putting patient at unacceptable risk for severe, irreversible toxicity: must balance risk of toxicity with increased dose to achieve maximal response
How do we prevent organ rejection
Giving pre-transplant screenings, and anti-rejection medications after transplant
Grade 1 irAE: Grade 2 irAE: Grade 3 irAE: Grade 4 irAE: what do you do?
Grade 1 irAE: continue therapy, no CCS needed, monitor closely Grade 2 irAE: delay immunotherapy, use topical CCS for skin rash, resume once improved, use PO systemic if gets more severe (persists) Grade 3 irAE: discontinue immunotherapy, provide systemic Oral CCS -- slow taper for at least 1 month Grade 4 irAE: discontinue immunotherapy, give Inpatient IV CCS -> slow taper for at least 1 month **sometimes even discontinue immunotherapy permanently
- Starts with weakness or tingling in the legs - May spread to arms and face - Chest muscles affected in 20-30% of people - Peak deficits within 2-4 weeks after onset - Most people fully recover This is the clinical presentation of:
Guillan-Barre Syndrome
What makes HIV a chronic disease state where medication cannot be discontinued throughout the patient's entire lifetime (as of now)
HIV Reservoirs
Why can't we discontinue HIV medication once achieving an undetectable viral load
HIV Reservoirs: - HIV can hide in latent/resting cells where it is not yet replicating but has infected. (ex: macrophage, GI cells, CNS, Kidneys) - If medication is continually taken, these resting cells will be kept in their "reservoirs" and stay latent (hiding/not replicating) - If medication is discontinued the HIV will emerge out of the resting-state/out of the reservoirs and begin to replicate again and infect cells --> viral load spikes again
Why do you see lymphadenopathy as an initial HIV symptom?
HIV is moving through the Dendritic Cells into the lymph nodes and causing this inflammation/inflammatory response because all of the immune cells are migrating to the lymph nodes to recognize the HIV
Why can we develop an influenza vaccine and not an HIV vaccine?
HIV mutates in patients and so each patient would need their own vaccine. Not like the antigenic shifts seen with influenza.
Why will HIV always win when put up against CD4 cells
HIV replicates 100 billion times a day, CD4 cells generate 1-2 billion times/day --> once HIV infects the CD4 cells, CD4 cell death occurs. CD4 cells are outnumbered, much more HIV replication is occurring than there is with CD4 cell replication
For patients in whom there is a strong clinical suspicion of acute HIV infection, but initial testing with the HIV-1/2 antigen-antibody immunoassay is negative, additional testing should be performed with
HIV-1 RNA assay
Can immunocompromised patients be vaccinated with influenza and pneumonia vaccines to prevent infections?
HIV-infected patients or immunocompromised patients would have a higher incidence of these types of infections: pneumonias, flu, meningitis so they should absolutely be vaccinated for a lot of these infections in general We also know that vaccines require your immune system to develop an antibody response/develop an immune response to that vaccine and we know that HIV patients typically have a very weakened immune system. But, even though you may get less efficacy from the vaccines, because of HIV patient's high risk of infection you do want to ensure that they still receive all of their routine vaccinations - including pneumonia/influenza We want to avoid giving live vaccines to HIV-positive patients but we can give inactive vaccines in general.
Two main celiac disease genes (pathophysiology)
HLA haplotypes 1. DQ2 (90%) 2. DQ8 (10%) implicated
Most important toxicity to consider with VEGF Inhibitors? Mechanism?
Hypertension Mechanism: Inhibit the release of nitric oxide thereby inhibiting the ability to vasodilate, effectively resulting in vasoconstriction which will increase BP most important toxicity to remember with VEGF inhibitors
High-Dose Interleukin Therapy Toxicities: patients are at risk for capillary leak syndrome when taking high doses of interleukin-2, what are the symptoms of capillary leak syndrome?
Hypotension Dyspnea Renal dysfunction
Managing Toxicity of Interleukin-2 therapy (cytokine therapy)
Hypotension/oliguria/rising SCr: fluid, vasopressors Metabolic acidosis: sodium bicarbonate Dyspnea and peripheral edema: Diuretics Fever/chills/muscle aches: pre-medicate with APAP, NSAIDs --> treat with Meperidine (rigors/chills) N/V: pre-medicate and treat with 5HT3-RA(ondansetron) or Olanzapine (dopamine antagonist) do not use steroids- suppress more Skin, rash, pruritus: antihistamines, emollients Cardiotoxicity: consider rate-controlled agent
Creators of Checkpoint inhibitors were recently awarded the Nobel Prize in 2018 for their discovery of cancer therapy via:
INHIBITION OF NEGATIVE IMMUNE REGULATION (inhibit inhibition of anti-tumor response )
Why was the 1st successful kidney transplant in the 1950s so successful, given that the transplant donor and recipient were identical twins?
Identical twins have identical genetic makeups: therefore, the recipient twin did not elicit an immune response because the transplanted organ was not seen as "foreign"
31 y/o F with no PMH No medications Social History -No IVDU -Sexually active with 1 partner 1st sexual encounter was last night CC: This morning TB was informed that her partner is HIV positive TB's last HIV test was 1 month ago and negative Patient presents to HIV clinic to see if she is infected, What tests can be run for this patient?
If we test the patient today we are not going to be able to detect her exposure (last night), we will only be able to establish a "new baseline" for her, to see if she was infected prior to last night's encounter --> even though her last test was one month ago, she could've been in the eclipse period 1 month ago! Eclipse period: she was tested negative but no one ever tested her NAT test: could she have truly been positive during that test one month ago - Use a rapid antibody test today to identify if the patient was infected prior to last night's encounter
Antibody that mediates immediate anaphylaxis
IgE
What is the main difference between an autoimmune disease and hypersensitivity reaction?
IgE is not involved in autoimmune diseases
Type of infusion related reaction that is due to a "true allergy"
IgE-mediated infusion reaction
Why is hypogammaglobulinemia (low IgG) a delayed-toxicity of CAR-T cell therapy?
IgG is produced by B-cells, our current CAR-T cell therapies are B-cell targeting (ALL, B-cell Lymphoma). CAR-T cell therapy is extremely potent therapy that depletes all of our B-cells that are CD19 positive (the majority of our B-cells) Therefore, there are now no more B-cells capable of producing plasma cells to produce IgG antibodies -- body doesn't have anymore IgG antibodies -- hypogammaglobulinemia
Antibody-Mediated Rejection Immune Cells Responsible: Timing: Treatments: Effectiveness of Treatment:
Immune Cells Responsible: B-cells Timing: Hyperacute (immediately after perfusion) Acute (first 1-2 months) Chronic (up to even 10 years after transplant) Treatments: Plasmapheresis IVIG (intravenous immune globulin) Anti B-cell Agents Effectiveness of Treatment: more difficult to treat than cellular rejection (t-cells)
Cellular Rejection Immune Cells Responsible: Timing: Treatments: Effectiveness of Treatment:
Immune Cells Responsible: T-cells Timing: acute (first 1-2 months), chronic (even 10 years after transplantation) Treatments: methylprednisolone (steroids), Anti-thymocyte globulin (T-cell depleting induction agent) Effectiveness of Treatment: easier to treat than Antibody-mediated rejection
How does HIV infection effect B-cells? (2 main effects)
Impacts B cells without truly infecting or killing them directly: 1. pro-inflammatory factors in HIV infection can cause the dysregulation of B-cells 2. destruction of CD4 T-cells prevents further B-cell production
Avoid use of checkpoint inhibitors in patients with autoimmune conditions, why?
In patients with chronic autoimmune conditions - may actually exacerbate their autoimmune condition because we are essentially inducing an autoimmune status with the use of checkpoint inhibitors (activating T cells) --> exacerbate that T cell for the autoimmune disease that they may have as well
Gemtuzumab ozogamicin Indication: Classification: Target: Cytotoxic Agent: Dose limiting toxicities:
Indication: AML Classification: Humanized Target: CD33 Cytotoxic Agent: Calicheamicin (DNA disruption) Dose limiting toxicities: hepatotoxicity (including veno-occlusive disease, hemorrhage, myelosuppression
Ado-trastuzumab emtansine Indication: Classification: Target: Cytotoxic Agent: Dose limiting toxicities:
Indication: Breast Cancer Classification: Humanized Target: HER-2 Cytotoxic Agent: DM-1 (microtubule inhibitor) Dose limiting toxicities: hepatotoxicity, embryo-fetal toxicity
Brentuximab vedotin Indication: Classification: Target: Cytotoxic Agent: Dose limiting toxicities:
Indication: Hodgkin's Lymphoma Classification: Chimeric Target: CD30 Cytotoxic Agent: MMAE (microtubule inhibitor) Dose limiting toxicities: peripheral neuropathy, myelosuppression, hepatotoxicity, renal impairment, BBW = progressive multifocal leukoencephalopthy
Belatacept Indication: MOA: Dosage Form: Adverse Effects:
Indication: Maintenance (Signal 2): prevents co-stimulation MOA: prevents co-stimulatory signal required for T-cell activation by binding to CD80 and CD86 on APCs and blocks the interaction with CD28 on T-cells preventing T-cell activation! Dosage Form: IV therapy Adverse Effects: well tolerated
When an HIV infected patient progresses to chronic infection they can often be asymptomatic, why?
Individuals with primary infection progress into chronic infection where extensive CD4 T-cell death and CD8 cell evasion has occurred. B cell antibody production may occur but pro-inflammatory factors during infection cause dysregulation of existing B cells and death of CD4 cells prevents further B cell production therefore prevention of further antibody production - lack of immune response = lack of symptoms!
ATGAM Basiliximab Antithymocyte Globulin Alemtuzumab Are all _______________ agents, administered at the time of transplant in high doses for a short-period of time, usually 1-3 days.
Induction agents
Once infected with HIV, the virus targets CD4 T-cells and monocytes, how does it do this? (what surface-level interactions are at play)
Infects Helper (CD4) T-cells and Monocytes: - T-cells: HIV's surface glycoproteins, gp120 and gp41 bind to theCD4 receptor molecules and CXCR4 receptors on the surface of T-cells - Monocytes: gp120 and gp41 of HIV bind CXCR5 (chemokine receptor) on the surface of monocytes for entry (see picture)
vancomycin hypersensitivity is a result of
Infusion of vancomycin leads to direct release of histamine from mast cells and basophils causing itching and a rash of the face, neck and upper torso (pseudo-allergic reaction)
Atezolizumab, Avelumab and Durvalumab are all agents that
Inhibit PD-L1 on the tumor cell surface --> prevent the PD-L1 ligand from binding the programmed-cell death receptor (PD-1) on the T-cell surface--> prevent "Hiding" by tumor cells--> tumor cells are marked for cell death
MOA of Calcineurin Inhibitors
Inhibit signal 1 of T-cell response: - Calcineurin inhibitors bind their targets to form a complex with calcineurin - Calcineurin is then unable to activate factors in the cell signaling pathway - This prevents signals for nucleic acid transcription and translation - This leads to reduced synthesis of interleukin-2 and activation of its receptor - Ultimately blocks T-cell activation TCR inactive --> unable to bind antigen presented by APC --> unable to be activated --> signal 1 blocked
mTOR inhibitor mechanism of action
Inhibiting agent enters the T-cell and binds to its target (immunophilin FKBP12) in the cytoplasm, thereafter this complex binds to and inhibits mTOR to inhibit the cell cycle---> Prevents T-cell proliferation (Signal 3)
Pathophysiology of an IgE-mediated Infusion reaction
Innate antibodies develop against the mAb during first exposure (IgE). Upon 2nd exposure to the mAb (2nd or later infusion), the antibodies developed from the first infusion create a large inflammatory response - Re-challenging the mAb is NOT feasible.
Rejection can occur at various times throughout transplantation, but in efforts to prevent rejection immediately at perfusion, _______________________ is used to prevent early rejection at the time of transplantation. This is known as____________
Intense immunosuppression is used --> Induction
Treatment of Antiphospholipid syndrome in patients with previous VTE
Lifetime anticoagulant therapy: warfarin
susceptibility to autoimmune disease is more strongly associated with which genotype?
MHC: Major histocompatibility complex gene --> MHC = self-surface molecule that mediates immune cell interactions ex: - Type 1 DM, addison's disease, grave's disease, SLE, RA, MS - some associated wth protection against autoimmune disease
HIV can infect/ kill off macrophages, what happens as a result?
Lose the ability to present antigens to other T cells for recognition and for activation of your immune system
B cell
Lymphocyte that matures in bone marrow; forms memory cells (adaptive immunity) and plasma cells
anergy
Lymphocytes fail to respond to their specific antigen - This occurs mainly when lymphocytes do not receive the appropriate signals that are needed for them to proceed with/undergo clonal expansion
What is activation induced cell death
Lymphocytes have intrinsic limits to proliferation and survival therefore --> there are autoreactive cells that may become activated but then undergo apoptosis ultimately --> there can be different barriers and mutations in this pathway (which normally would result in apoptosis) --> ultimately resulting in autoimmunitiy
HIV medications have no direct effect on the regeneration of CD4 cells, how then do they allow CD4 count to increase?
MOA: prevent HIV replication--> specifically by inhibiting the HIV replication cycle --> does not kill virus just prevents further virus from developing --> HIV RNA gets replaced every 3 days --> if no more HIV virus is spreading/replicating and HIV RNA's inability to replicate in 3 days will cause cell death --> viral load decrease --> CD4 cells increase --> decrease load to undetectable levels
Cyclosporine Tacrolimus Mycophenolate Sirolimus Azathiopurine Corticosteroids Belatacept are all _____________ agents, administered to patients post-transplant at the lowest effective dose for long-term (usually for the remainder of the life of the transplanted organ)
Maintenance agents
Management of HER-2 decrease in LVEF- if heart failure occurs
Management: if heart failure occurs, we would just manage heart failure per current guidelines for heart failure -- nothing unique/specific about the management of heart failure in HER-2 mAbs vs. normal Consider holding HER-2 mAb until the LVEF resolves Wouldn't re-challenge until the LVEF resolves: if it never resolves, than permanently discontinue
Cytokine Release Syndrome Mechanism: Symptoms: Treatment:
Mechanism: T-cell activation and the release of cytokines thereafter leads to the activation of leukocytes, including T-cells, B-cells, NK cells, macrophages, dendritic cells, monocytes Symptoms: anaphylaxis, fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, headache Treatment: - Discontinue therapy OR - Slow infusion rate, and give corticosteroids, antihistamines, and analgesics
Serum Sickness Mechanism: Symptoms: Treatment: When does it occur relative to Anti-thymocyte Globulin Induction therapy?
Mechanism: Type III Hypersensitivity reaction to proteins from a non-human source -->Accumulation of donor antigen-recipient antibody complexes that cannot be cleared by innate immune system causes an inflammatory response Symptoms: fever, rash, arthralgia, myalgia, hypotension, malaise Treatment: Discontinue therapy (infusion) and give CCS, antihistamines and analgesics When does it occur relative to Anti-thymocyte Globulin Induction therapy? 5-15 days after 1st dose (up to 2 weeks after first dose!)
Cytokine therapies are primarily used to manage what type of cancer
Melanoma
Siroliumus and Everolimus Metabolism: Elimination: Adverse Effects:
Metabolism: CYP3A4 and CYP3A5 Elimination: 80-90% fecal Adverse effects - Poor wound healing - Bone marrow suppression (low white blood cells, red blood cells, platelets)
pathophysiology of cytokine-mediated infusion reactions?
More commonly low grade, due to the release of pro-inflammatory cytokines when a mAb binds to its target. Occurs typically during the first infusion - re-challenging mAb = feasible
Why is it important to make sure donor and recipient blood types are compatible? (what are we trying to prevent)
Must make sure the donor and recipient blood types are compatible to prevent hyper-acute (immediate) transplant rejection - successful transplant: organ will get perfused with blood, turn pink - good blood flow - no blood type rejection - rejected transplants: organ will turn purple/black within a matter of minutes due to hyper-acute rejection - blood perfused prevented
CD8 cytotoxic T-cells can stabilize the viral load. How does HIV overcome this stabilization during disease progression?
Mutations in HIV virus that allow it to HIDE from the CD8 cells
Is re-challenging of mAb feasible after IgE-mediated infusion-related reaction?
NO, NOT FEASIBLE, in IgE mediated reactions re-challenging (giving mAb again) would not be feasible or advised unless we were to do a desensitization protocol
HIV-1 Antibody/antigen (-) NAT (-)
Negative for HIV-1
Specificity of diagnostic test
Negative results are really negative -- a negative result (seronegative) is truly negative: no potential for seroconversion
induction agents that target activated T-cells, and inhibit T-cell proliferation and differentiation, but do not cause T-cell lysis
Non t-cell depleting agents
Why is interferon-alpha not the treatment of choice for any cancer?
Not curative for any tumor/cancer type Associated with substantial toxicity
Direct Apoptosis or Growth Inhibition of mAbs
Occurs when the antigen-binding site of the mAb (Fv region) binds to the antigen of the cell, causing inhibition or activation of an intracellular process that either stops tumor growth or promotes tumor death
cytokine release syndrome
Once a T cell is activated, it releases signaling molecules called cytokines that help activate the immune response; If levels of cytokines rise too high, it can stimulate an inflammatory response throughout the whole body that can be detrimental to the patient's health
How does complement activation work in response to antibodies?
Once antibodies are produced, they can bind to the part of the transplant (via Fab region) and activate the complement cascade (via Fc region), which ultimately results in channel formation (holes) in the transplant cell (membrane attack complex), causing cell lysis and death
- Systemic lupus erythematosus - Rheumatoid arthritis - Antiphospholipid syndrome - Sjögren's syndrome are all examples of __________ where multiple organs are involved; characterized by chronic activation of innate and adaptive immune responses
Organ non-specific (systemic) autoimmune diseases
- Grave's disease - Type 1 diabetes mellitus - Multiple sclerosis - Guillan-Barre syndrome - Acute rheumatic fever - Celiac disease are all examples of __________ where inflammation and autoantibody production is contained to one organ
Organ specific autoimmune diseases (T-cell or antibody mediated)
How do tumors grow unchecked by our immune system
Our innate immune system perceives most cancers as "self"
Nivolumab, Pembrolizumab and Cemiplimab are ________________ checkpoint inhibitors that work by________
PD-1; Inhibiting PD-1 on the T-cell surface prevents the interaction of the T-cells PD-1 (programmed death receptor) with the PD-L1 ligand on the tumor cell surface which would result in inactivation of the T-cell and effective evasion of the immune response by the tumor cell. - Inhibition allows for anti-tumor activity --> tumor cells are recognized
Sipuleucel-T MOA
Peripheral blood is collected from the patients and the patient's own APCs are isolated from that blood. The manufacturer takes those APCs and attach it with this protein called PA2024. This protein consists of a prostate antigen, as well as other components. Because of that prostate antigen, when they re-infuse those cells back into the patient, the modified-APCs with that prostate antigen already on it can now stimulate T-cells to attack the prostate cells directly.
Mature lymphocytes that encounter self antigens in the periphery may undergo deletion, anergy, or ignorance
Peripheral tolerance
Reasons to hold Interleukin-2 therapy at least until the toxicities have resolved - potential contraindications
Persistent lethargy, somnolence Rash Arrhythmias Hypotension Renal dysfunction, metabolic acidosis Bowel perforation Infections and sepsis
What FDA approval revolutionized transplants allowing for much lower rates of transplant rejection?
The approval of Cyclosporine (Calcineurin Inhibitor) to prevent organ rejection!
Pathophysiology of Guillan-Barre Syndrome
Post-infectious immune response against pathogen (ex: Campylobacter jejuni, Haemophilus Influenzae) - May also occur after surgery or vaccine (less common)
Monoclonal antibody nomenclature
Prefix (drug-specific prefix, determined by the manufacturer, doesn't really have anything to do with the antibody itself) Antibody Target: Tu = active against tumor, therefore the mAb is used in cancer immunotherapy --- tumor directed Ci = cardiovascular --> mAbs that have an effect on the cardiovascular system Li = immune-directed (common in our immunotherapies such as checkpoint inhibitors - PD-1) Antibody Source: the ratio of murine (mouse-derived) vs. human-derived components Mo = murine (100%): highest risk of infusion related reaction, entirely foreign Xi = chimeric: large portion human-derived, still significant murine component: high likelihood of infusion-related reaction Zu= (ex: trastuzumab): humanized mAb therefore, largely human and just a very small portion of mouse-derived antibody U = 100% human: least likely to cause an infusion reaction Suffix: mab All monoclonal antibodies will end in mab
What is the role of follicular dendritic cells in immune response to infection
Present in the lymph nodes in order to stimulate your immune response --> specially serving to activate B cells
Clinical presentation of Antiphospholipid syndrome
Presents as a prothrombotic disorder that may lead to vascular thrombosis or pregnancy complications - DVT - Peripheral arterial thrombosis - PE - Stroke
What is the overall goal of HIV treatment?
Preventing AIDS: give patient HIV mediation so that their CD4 counts never drop below 200
Metabolite of Arachidonic acid, can cause bronchoconstriction and vasodilation (as well as the exact opposite)
Prostaglandins
What are HLA proteins? Where are Class I found? where are Class II found?
Proteins on the surface of WBCs and other tissues that serve to recognize antigens as non-self - Class I: present on all nucleated cells - Class II: present on cells with immune function --> APCs such as dendritic cells or B cells, macrophages
The typical signs and symptoms of an infection are high WBC count and fever (pyrexia). Why may you not observe these symptoms in an immunocompromised patient with HIV that is experiencing an infection, even a potential life-threatening OI? Pyrexia: High WBC count:
Pyrexia: occurs because of the pyrogens -->cytokines are released by your immune system in response to pyrogen presence --> causes temperature rise to occur (as we know PG synthesis -->hypothalamus --> adjustment of temperature set point) HIV can block cytokine release which essentially diminishes pyrexia or fever seen during infection. Diminishes your ability to mount a temperature in response to infection Increase in WBC count: WBC counts are your immune cells, and HIV is actively destroying your immune cells therefore you will not be able to mount the same type of WBC count response to an infection when you are immunocompromised with HIV --> WBC COUNT MAY ALWAYS BE LOW
How are BBW toxicities (Cytokine release syndrome, neurologic toxicities) accounted for before starting Blinatumomab therapy?
REMS Program: - essentially mandating a communication between providers about toxicities related to Blinatumomab to make sure that providers fully understand these toxicities before giving the drug - Also: the risk of preparation and administration errors with the drug
CENTRAL TOLERANCE Receptor Editing
Receptor editing is a process that occurs during the maturation of B cells, which are part of the adaptive immune system. - Forms part of central tolerance to attempt to change the specificity of the antigen receptor of self reactive immature B-cells, in order to rescue them from programmed cell death, called apoptosis. - creation of new receptor with different (non-self) antigen specificity on B-cell to prevent programmed cell death
Signal 1: T-cell recognition in transplantation
Recipient T-cells recognize donor antigens that are presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells
Complement-dependent Cytotoxicity of mAbs (3 pathways)
Recruitment of Complement via the antibody's Fc region that can exert its action via 1 of 3 pathways: 1. Complement can recruit T cells and result in a direct cell lysis - similar to the ADCC pathway- 2. Complement could produce a MAC porin -- resulting in cell lysis directly from the complement 3. Complement could cause opsonization which could mark these cells better for that cell lysis by the immune system
Place in therapy for Blinatumomab
Relapsed/Refractory ALL (minimal residual disease positive) ALL -->first and only therapy to demonstrate superior overall survival in this patient population (ALL population)
What is the difference between acute and chronic HIV infection? How many weeks following initial exposure do the acute and chronic phases of infection occur?
SEROCONVERSION: Whether or not your body has developed antibodies or not - It can take up to 4-8 weeks for antibody production to occur to a detectable level - Acute: occurs from 0-12 weeks of infection - Have not yet developed antibodies towards immune cells or HIV proteins - Primary infection, initial infection - Chronic: > 12 weeks of infection - You have developed antibodies
What is the difference between Serum Sickness and Serum Sickness-Like Disease?
Serum Sickness = Type III reaction due to antisera (non-human derived serum) Serum Sickness-Like Disease: Type III reaction to other things that antisera
Order the following from highest rejection risk (requires more immunosuppression) to lowest rejection risk (requires less immunosuppression): Heart, Liver, Lung, Small Bowel, Pancreas, Kidney
Small bowel > lung > pancreas > heart > kidney > liver
How to treat cytokine release syndrome and neurologic toxicities associated with Blinatumomab therapy?
Steroids +/- Tocilizumab (IL-6 Inhibitor) - less cytokine release
Immunosuppressive Regimen or Immunosuppression
Sum of all the medications used to suppress the immune system in order to prevent or treat rejection
Grade 2 (Moderate) Infusion-related Reaction - Symptoms - Management
Symptoms: involves > 1 organ system, mild symptoms, PLUS: hives, angioedema, chest tightness, or dyspnea BUT LACKS SIGNIFICANT HYPOTENSION OR OXYGEN DESATURATION ADD: additional antihistamine therapy: H-1 - diphenhydramine 25 mg IV once H-2 Famotidine 20 mg IV once CCS: Hydrocortisone 100 mg IV once) Bronchodilator (albuterol) if dyspnea is occurring - Consider epinephrine 0.3 mg IM/SQ when symptoms resolve, consider restarting mAb infusion at a slower rate
Checkpoint inhibitors inhibit PD-1, PD-L1 and CTLA-4 which allows for
T-cell activation --> tumor cells are no longer able to evade immune response and get marked for cell death
______________ agents cause cell death and more toxicity in induction therapy (but slightly more efficacious due to bigger response) whereas ________________ agents do not cause cell death (work on activated T-cells) and are better tolerant (not as potent immunosuppressants)
T-cell depleting; Non T-cell depleting
Acute cellular rejection is mediated by
T-cells
Which cells are responsible for cellular rejection after transplant?
T-cells
Helper T cells
T-cells with CD marker CD4, and help stimulate the production of CD8 T cells and B cells after being activated by an antigen
What role do CD8 T-cells play in HIV Infection?
TCRs and CD8 T cells: - Recognize HIV proteins on the cell surface using their MHC 1 and induce cell lysis as a result (aim to lyse all of the infected cells) -Release cytokines which inhibits further viral replication of HIV
Which is used more often Cyclosporine or Tacrolimus?
Tacrolimus
CAR-T cell MOA
Take blood from the patient and instead of taking their APCs, actually isolate the T-cells specifically. When we isolate the T-cells from the patients blood sample we modify those T-cells to have receptors on them for the cancer cell directly. Before infusing the modified cells back into the patient, we allow them to grow: --T-cell clonal expansion - This is so, once they go back in the body we don't have to wait for the T-cells to expand like we did with Sipuleucel-T. --> T-cells are already active because we did that in the lab beforehand. Once millions of CAR-T cells are grown in the lab, then we re-infuse it back into the patient and since it is T-cells that we modified, they can directly attack the cancer cell and produce a very quick cell killing, very quick cancer cell death.
What body sites possess immunologic privilege? What is immunologic privilege? Why is it good? Why could it be problematic?
The brain, uterus, eyes and testes are "immunologically privileged" meaning that they can tolerate introduction of antigens without eliciting immune response (via physical barriers: BBB, active mechanisms like FasL pro-apoptotic protein modulation). It can be helpful because it allows non-renewable tissues (like neurons) to not be damaged by immune responses but it also can be dangerous because invading pathogens may not be removed.
Autoimmunity definition
The generation of lymphocytes or antibodies which react with the body's own constituents
What is the rationale behind giving some cancer patients an allogeneic stem cell transplant?
The immune system has the opportunity to eradicate cancer, and the "allogenic" stem cell transplant will serve as a "new" immune system for the patient, capable of recognizing the cancer as foreign
Graft/Allograft
The organ that has been transplanted
Donor
The patient who has donated the transplanted organ
Positive Crossmatch
The recipient does have an antibody present for the donor's HLA
Set point of HIV infection
The relatively stable HIV RNA level reached about 1 to 2 months after the peak HIV RNA levels associated with acute HIV infection. Without antiretroviral therapy, the HIV RNA levels tend to chronically remain near the set point established early in HIV infection
Eclipse Period of HIV Infection
The short interval following HIV acquisition in which no diagnostic test is capable of detecting HIV. This interval is typically 10 to 12 days in duration and the HIV RNA is the first test to detect HIV
For what duration must maintenance therapy be administer to a patient that has received a transplant?
Therapy must be continued as long as the patient has the organ
Negative Crossmatch
There is no antibody present for the donor's HLA: okay to transplant
Why are checkpoint inhibitors usually used for less aggressive diseases?
They have a delayed onset of effect --> Durable response but ~3 months to onset! since we know it will not work fully for at least 3 months! --> a disease that is rapidly dividing and very aggressive and requires rapid cell-kill --> checkpoint inhibitors will not be the best option! Regardless of whether it is technically indicated or not we would want to avoid more aggressive diseases just knowing that it will take months to work
A derivative of a specific prostaglandin that causes platelet aggregation and regulates coagulation
Thromboxane
In HIV diagnostics, an antibody-antigen test is always preferred to be used first over an antibody test. Why?
To be able to detect HIV sooner rather than later: - antibodies detectable as early as 25 days after exposure - p24 antigen detectable as early as 15 days after exposure!
What role does one's immune response play in the case of a transplant? (what we want to prevent)
To be able to identify the transplant as non-self and has the ability to destroy the transplant (rejection)
order the following dosage forms from highest risk of HS reaction to lowest risk: - oral - IM - IV - topical
Topical > IV = IM > oral
Managing Toxicity of Interferon Therapy (cytokine therapy)
Toxicity 1: delusions, visual hallucinations,: focus is on management rather than prevention Management: Lorazepam (benzodiazepine), Haloperidol (antipsychotic) Toxicity 2: depression Management: Antidepressants -- we often try to prevent depression with the use of antidepressants particularly if we have identified a patient as high risk for depression Toxicity 3: fatigue Management: hydration
Allogeneic stem cell transplant
Transfer of stem cells from a donor to another person - In cancer: essentially giving the cancer patient someone else's immune system which will recognize the cancer as foreign and kill cancer cells (cancer selectively hides from host immune cells)
Signal 2: T-cell Co-stimulation (what are the 2 distinct signals that the T-cell must receive to be activated)? What occurs thereafter if both Signal 1 and Signal 2 occur?
Two distinct signals: - Signal 1: The donor antigen is presented to the recipient T-cell by an APC and is recognized as non-self or "foreign" -Signal 2: co-stimulatory binding of APC CD80/CD86-receptor and T-cell CD28. Result: This then activates multiple signal transduction pathways: Ca2+ Calcineurin pathway, MAP kinase pathway, PKC pathway --> these signal transduction pathways then activate Transcription factors and the expression of interleukins (importantly interleukin-2)
Which blood type is the universal recipient (can receive from any blood type but can only donate to itself)?
Type AB: - has both A and B antigens on its surface (therefore can receive from type A, type B and type O and still not recognize the foreign blood as non-self) - Plasma with neither anti-A nor anti-B antibodies therefore will not mount an immune response to A or B antigens
HS reaction mediated by IgE antibodies
Type I
HS reactions that occur when IgE antibodies are produced after the immune system recognizes a Hapten (drug-protein combination presented as antigenic), and bind to effector-like cells (mast cells, basophils). Upon future exposure to the antigen, 2 or more IgE molecules on the Mast cell or basophils surface bind to the antigen, inducing the release of inflammatory mediators by mast cells/basophils such as histamine, LKTs, PAF.
Type I Hypersensitivity Reactions
Which blood type is the universal donor (can donate to any blood type but only receive from itself)
Type O: - has neither A or B antigens on the surface of RBCs (wont be recognized as foreign by other blood types) - Plasma has both anti-A and ant-B antibodies therefore will reject Type A, Type B or Type AB.
HVTN 702
Used a similar primer/booster component but changed the protein component from gp120 because of where the study was taken place There are various subtypes of HIV and they wanted to make the vaccine very specific to the subtype of HIV that is seen in South Africa ---> Subtype C 500 pts: vaccine Vaccine --> 129 seroconverted (became HIV +) 2500 pts: placebo Placebo --> 123 seroconverted (became HIV+) NO EFFICACY SEEN IN THIS STUDY OBVI -- study halted bc no efficacy seen Did provide more literature and basis of what needed to be done
Why do you see symptoms of lymphadenopathy during acute HIV infection?
Viral dissemination occurs about 10 days after acute infection --> viral dissemination (systemic infection) where virus is being taken to various parts of the body (including your lymph nodes)--> HIV being taken by Dendritic Cells into lymph nodes
Patient comes in 3 months after testing positive for HIV. We can assume they are in the _______ stage of infection. Why?
We can assume after 3 months of exposure they are likely in the chronic HIV infection stage Its been over 3 months, they're currently positive and they should have already seroconverted at this point (25 days) - made antibodies
Induction Medications When administered: Dose: Duration of administration:
When administered: at the time of transplant Dose: high dose Duration of administration: short-term, usually 1-3 days
Maintenance Medications When administered: Dose: Duration of administration:
When administered: post-transplant Dose: lowest effective dose - to prevent ADR Duration of administration: long-term, usually for the remainder of the life of the organ
How long after exposure do Type I reactions typically occur?
Within minutes-hours, but may occur up to 72 hours afterwards. - A reaction that occurs after > 72 hours can still be mediated by IgE but the later a reaction occurs, the less likely it is to be a Type I reaction
What does it mean that pembrolizumab has a basket indication
You could have ANY type of cancer, (bladder, colorectal, lung . . . Etc), it does not matter what type of cancer you have ALL YOU NEED TO HAVE IS THIS MICROSATELLITE INSTABILITY MARKER!! MSI: molecular marker that if present, regardless of cancer type, Pembrolizumab can be used
Signal 1 APC presentation to T-cell with the absence of co-stimulatory CD-CD signal 2 leads to:
a state of T-cell non-responsiveness (anergy) where T-cells can recognize antigens through the T-cell receptor but fail to mount a functional response
Functional cure
a treatment that suppressed the virus to the point that it cannot cause illness and is undetectable by tests
Drug-induced vasculitis
a type of Type III Hypersensitivity reaction where the immune complexes are deposited in blood vessel walls causing local inflammation and subsequent tissue injury (most commonly in lower extremities, but can occur anywhere in the body)
MOA of antibody-drug conjugates
antibody binds a specific marker (antigen or receptor) on the cancer cell but then the cytotoxic agent that is attached to the antibody is designed to be released in the tumor cell and kill the tumor cell once internalized Essentially: combining the specificity of mAbs --> and the ability to directly target a specific cell that has a specific marker with a super toxic warhead that can be then released in the tumor cell
Most common reason anaphylaxis causes death
asphyxia due to airway obstruction either at the larynx or within the lungs
Condition where the autoimmune process contributes to the pathogenesis of disease (how the disease arises)
autoimmune disease
1st degree relatives with Hashimoto's diseases show high incidence of thyroid antibodies and of overt and subclinical thyroiditis --> this is an example of how
autoimmune diseases aggregate in families (genetics)
what is the limitation to skin testing for penicillin allergy
can only determine if a pt has an immediate (Type I) hypersensitivity reaction, cannot diagnose Type II, III or IV
Most cells of the body can become directly or indirectly in allergic reactions, how do platelets and vascular endothelial cells become involved?
can release inflammatory mediators (histamine, PAF, leukotrienes, PGs, TXA2s, complement)
hives, pruritus, flushing, swollen lips/tongue, respiratory compromise, hypotension
clinical presentation of anaphylaxis
- Tartrazine (dye) - Sulfites (antioxidants in foods and drugs) - Benzoates (preservatives) - Parabens (biocidal agents) are all _______
common excipients with reported allergic rxns
How can we assess association of one's MHC genotype with autoimmune disease?
comparing alleles in patients with disease to alleles in patients without disease Example of type 1 diabetes - HLA genotypes of diabetic patients are not representative of those found in the general population - DR 2 protects against development of Type 1 diabetes - Almost all type 1 DM have DR 3 or DR 4--- basically the point is that MHC genotype can be a large contributing factor to different types of autoimmune conditions
Types of donors? When is each more common?
deceased or living; - deceased is more common in general - living is more common in the case of kidney and liver transplant: - patients only need one kidney - can donate - patients can opt to donate a part of their liver to someone with end-stage renal disease (the liver is capable of regenerating)
Toxicities are checkpoint inhibitors are all ______ toxicities
delayed toxcities Dermatitis: weeks 4-10 (doses 2-4) Colitis: weeks 5-10 Hepatotoxicity: weeks 6-14 Pancreatitis/diabetes: weeks 6-20 (mentioned in NCCN) Thyroid: weeks 6-20 (mentioned in NCCN) Pneumonitis: ~week 10 (mentioned in NCCN)
Role of IgG and IgM antibodies in allergic reactions
destruction of cells and tissues involved in anaphylaxis
What is self-tolerance
developed lack of responsiveness to one's own antigens either through central tolerance or peripheral tolerance
Is NSAID-related GI ulcer a dose-dependent or dose-independent ADR?
dose-dependent ADR
Is NSAID-related Anaphylaxis a dose-dependent or dose-independent ADR?
dose-independent: anaphylaxis could occur with even a tiny dose of the drug
When do cytokine-mediated infusion-related reactions typically occur?
during the first infusion
When do IgE mediated infusion reactions occur>?
during ≥2nd infusion with a mAb after the patient has already developed antibodies against the antigen of the mAb
How early can newer HIV antibody tests detect ANTIBODIES ?
early as 25 days (3 weeks) after infection
HVTN 505
failed study but one of the first studies that showed that you can use a booster to be able to increase your immune response! --> used an adenovirus vector with an HIV antigen --> definitely showed that a priming vaccine with a booster was effective
VaxGen AidsVax trial (1998-2003)
failed therapy but showed that there was some efficacy of a humoral response in patients who were on this - vaccine to B envelope of gp120
how long should pts be monitored after experiencing an anaphylactic reaction? why?
for at least 12 hours: potential late-phase reaction --> anaphylaxis can reoccur 6-8 hours hours after exposure to the antigen
Desensitization
giving very high and intense doses of immune suppression to try and overcome that reaction that is occurring
VEGF Function
helps promote the angiogenesis, and blood flow to the tumor cell to promote tumor cell growth
HIV
human immunodeficiency virus
Activation of CTLA-4 or PD-1/PD-L1 results in
immune evasion! - Tumor cells go "unnoticed" - Tumor cells upregulate PD-L1 to survive
What vaccines should HIV-positive patients receive? (live or inactive?)
inactive - We want to avoid giving live vaccines to HIV-positive patients but we can give inactive vaccines in general
opportunistic infections
infections seen in immunocompromised patients that would not typically occur in immunocompetent patients
immune system that is quick and non-specific
innate immune system - myeloid lineage --> granulocytes, platelets, RBCs
Negative skin test --> ___________ ---> _________
intradermal test (ex: PPD) ---> oral challenge test (typically with amoxicillin)
Why is aztreonam often given to patients in hospitals who report a severe penicillin allergy?
it is a β-lactam antibiotic and has close to 0% cross reactivity with penicillin
Types of organs viable for transplant
kidney, liver, pancreas, heart, lung, small bowel (intestine) most common = kidney and liver
What is tolerance?
lack of responsiveness to an antigen
What allergen is found in medical supplies, balloons, condoms, rubber toys, shoes and can cause allergic contact dermatitis, irritant contact dermatitis and immediate hypersensitivity reactions?
latex -- develops usually after prolonged exposure
Severity of Pseudo-allergic reactions
localized - systemic
Sjögren Syndrome pathophysiology
lymphocytes infiltrate the salivary and lacrimal glands --> - SS= a virus that promotes autoantibody production (molecular mimicry) --> production of autoantibodies interferes with muscarinic receptors in salivary/mammary glands --> chronic inflammation draws more immune cells to the site --> dry glands
Sirolimus and Everolimus are ______________agents which block the___________ signal of the T-cell response, inhibiting T-cell proliferation.
mTOR Inhibitors; Signal 3
most common symptom of Sulfa allergy?
maculopapular rash
why should patients d/c use of antihistamines for several days before penicillin skin testing?
may cause a false negative: positive reaction requires positive control -> histamine (they inhibiit)
T cells role in allergic reactions
mediate all 4 types of allergic rxns (Type I-IV)
MOA of interleukin-2 (aldesleukin) therapy
mimics our endogenous supply of IL-2 (recombinant form of endogenous IL-2), thereby acts by increasing the number of T-cells that are around, activates them and boosts more T-cell production. Ultimately, all of the above provides the T-cell resource that is needed to attack the cancer cell effectively
When will a positive HIV antigen (p24) test become detectable?
minimum of 15 days post-exposure (little after 2 weeks)
In transplant, the ______HLA (A, B, DR) that match, the _____ chance of rejection
more;lower --> inherited as a "set" --> one set from each parent (A,B,DR from each parent), there are only so many different combinations that children can have from the same two parents
purpose of saline in penicillin allergic rxn
negative control - do not expect rxn to occur
side effects of calcineurin inhibitors
nephrotoxicity, neutrotoxicity
will sulfonylarylamines and nonsulfonlarylamines likely cross-react?
no - unlikely due to differences in chemical structures
Why does peripheral tolerance need to exist?
not all potential self-antigens that could lead to autoimmune disease are produced in the central lymphoid organs
Typically HIV is not what kills patients, it is the _____________that can develop as a result of immunocompromised state that can cause a high mortality
opportunistic infections: infections that occur in a immunocompromised patient that would be otherwise harmless in an immunocompetent patient
PAF effects on body? (3)
pain itching erythema
What patients cannot receive cytokine therapy
patients with abnormal cardiac and pulmonary function -- must be done in a specialized ICU hospital setting
Short-term side effects of prednisone
poor wound healing (transplant wounds could be problematic) hyperglycemia (ensure appropriate insulin regimen if pt has diabetes)
mTOR inhibitors side effects
poor wound healing, bone marrow suppression
SensiTivity of a diagnostic test
posiTive results are really positive is a positive result TRULY positive? -> never want to tell a pt they are negative when they may be positive in the end
You suspect a patient is having an HS rxn due to a drug allergy. You discontinue the drug therapy, what do you expect to occur thereafter?
reaction should stop as well --> d/c drug --> d/c reaction
Both serum sickness and serum sickness-like are ?
self-limiting after the offending agent is discontinued
fever, malaise, lymphadenopathy, rashes and joint pain are relatively general symptoms of ___?
serum sickness --> type of Type III (immune complex mediated) Hypersensitivity reaction
CDC recommendation for HIV testing for 13-64 year olds?
should be tested at least one time regardless of risk factors
T-reg T-cells (regulatory T-cells)
subset of T-cells that bind to the antigen and secrete cytokines that inhibit the immune response! (regulatory) - cytokine secretion also leads to inflammation and antibody production
angioedema
swelling of the face, extremities and airways that may lead to respiratory compromise by bronchospasm or asphyxia
Induction agents that actively cause T-cell lysis and death
t-cell depleting agents
What factors may determine the variation in required trough levels to maintain in Cyclosporine maintenance therapy for a particular patient?
the necessary trough levels can very based on: - what type of organ is transplanted - how long from time of transplant - DDI: Cyclosporine is metabolized by/substrate of CYP3A4 and CYP3A5, P-glycoprotein efflux pumps - ddi can determine how trough levels could become - other factors that place the patient at higher risk for immunosuppression
THE ULTIMATE GOAL FOR CANCER IMMUNOTHERAPY
to induce immunologic memory against a tumor --> it is difficult to induce immunologic memory against a tumor that continues to acquire mutations and allows for this "immune escape".
Paired kidney exchange
two different organ pairs can donate to opposite recipients in the case where there would be no reaction
Common reactions to β-lactams? (3)
urticaria, pruritus, angioedema
NSAID allergy
usually a pseudo-allergic reaction related to blockade of COX-1 and thereby depleted [PGE-2] and subsequent production of LKTs--> potent bronchoconstrictors
Onset of Type II (cytotoxic) reactions
usually after 7 days (1 week) after initiating drug therapy
What anticoagulant should you avoid when treating pregnant women with antiphospholipid syndrome?
warfarin
Avoid use of checkpoint inhibitors in patients on chronic immunosuppressive regimens, why?
we need our immune system functioning in order for checkpoint inhibitors to work, if we activate our T cells but then we have immunosuppression on board that inhibits those T cells, then our function/immune function and checkpoint inhibitors won't actually work
belatacept side effects
well-tolerated
seroconversion
when a patient was once negative and is now positive on a HIV antibody test (detectable level of antibodies have been made)
Rejection Treatment when administered: dose: duration of administration:
when administered: only with/in the case of rejection - used to eliminate immune response dose: high dose duration of administration: short-term
how long after starting a vancomycin infusion do symptoms of pruritus, diffuse rash, burning, discomfort, hypotension, dizziness, headache, fever, chills onset?
within 4-10 minutes of starting the infusion
Is re-challenging of mAb feasible after cytokine-mediated infusion-related reaction?
yes ---we can just use pre-medications during subsequent dosing to make sure that the infusion reaction doesn't happen again
Treatment for patients with Sjogren Syndrome with systemic symptoms
¨Immunosuppressants/anti-inflammatory drugs for refractory disease (e.g. TNF-α inhibitors, hydroxychloroquine)
Key points slide
•T-cells and B-cells are the primary immune cells responsible for rejection •The 3 signals that make up T-cell activation include: (1) recognition, (2) co-stimulation, and (3) proliferation •Blood types and HLA should be matched between donors and recipients to decrease the risk of rejection •Multiple immunosuppression agents are used in combination to prevent rejection and limit side effects •Immunosuppression increases the risk of many complications, including infection and malignancy
Vancomycin hypersensitivity Angioedema from ACE inhibitors Pruritus/hypotension from morphine are all examples of?
Pseudo-allergic reactions: mimic Type I and involve release of mediators from effector cells but are not antibody mediated Vancomycin hypersensitivity: infusion of vancomycin leads to direct release of histamine from mast cells and basophils causing itching and a rash of the face, neck and upper torso Angioedema from ACE inhibitors: thought to be related to bradykinin release Pruritus/hypotension from morphine: morphine can directly cause the release of mediators from effector cells (hence why pts may say they have a morphine allergy even though they can tolerate chemically similar medications - hydrocodone/oxycodone)
Pencillins commonly cause which two types of Hypersensitivity reactions? Which serious allergic rxn have they been associated with?
Type I and Type II (--> also associated with SJS! (type IV) - scary)
Type of HS reaction that is also known as an immediate-hypersensitivity reaction
Type I reactions
Allergic reaction that results in antibody-mediated cell destruction
Type II Reaction (Cytotoxic)
Which of the following is a result of a drug allergy? A. Insulin --> Hypoglycemia B. Metoprolol --> Total body rash C. Penicillin --> SOB
B and C: both total body rash and SOB are unpredicted by the drug's pharmacologic effects (hypoglycemia = result of insulin's pharmacologic effect)
How to confirm the diagnose drug fever?
If it is drug fever the fever should resolve (defervescence) within 72-96 hours after d/c the drug ---delays of 5-7 days have been observed
Onset of histamine effects vs. leukotrienes effect?
Leukotrienes effects slower to onset than histamine! (histamine = 1-2 minutes) --> but more potent, longer-lasting
Contrast the effects of leukotrienes on the body vs. histamine effects
Leukotrienes: more potent, longer-lasting bronchoconstriction than histamine, slow-onset of effect
Symptoms of serum sickness-like disease
Most commonly rash, followed by eventually generalized symptoms (fever, lymphadenopathy, arthralgias)
How can Type IV reactions be used for diagnostic purposes? What does this emphasize about the nature of Type IV reactions?
PPD Skin test: TB test: individuals who have been exposed to tuberculosis before (therefore have developed memory T-cells) will have a Type IV hypersensitivity reaction to the purified bacterial protein in the test This emphasizes that Type IV reactions are generally self-limiting and we only provide symptomatic treatment (steroids only for severeeee rxns)
Urticaria (wheel+flair reaction aka hives) Angioedema Bronchospasm SOB Rash with pruritus and/or Anaphylaxis are all symptoms of _________? How would you define anaphylaxis?
Type 1 (immediate, IgE mediated) HS reactions: anaphylaxis = when 2 or more BODY SYSTEMS are involved (ex: SOB and hypotension)
Serum Sickness
Type III reaction: an immune system response to proteins and compounds derived from non-human serum (those often used to treat infections)
Immune-complex mediated reactions
Type III reactions
what differentiates Type IV reactions from Type I-III?
Type IV reactions are mediated by T-cells without involvement from antibodies (The rest involved antibodies I-IgE, II-IgG/IgM, III-antibody-drug complex)
Onset of serum sickness (Type III rxn)? (after administration of non-human serum derived compound)
Typically 7-14 days after administration
