Oral Bio Exam 3 - transplantation, immunodeficiency, and cancer immunology

tumor (or neoplasm)

"...a collection of the clonal descendants of a cell whose growth has gone unchecked. When a tumor continues to grow and to invade healthy tissue, it is consider to be a cancer."

X-linked severe combined immunodeficiency

(X-linked SCID) where the defect is in gamma-chain of IL-2 receptor family (CD132). Out of the SCID disorders, this is a relatively common one. The gamma-chain of this cytokine receptor is shared by IL-2, -4, -7, -9, -11, and 15•lymphocyte development is abnormal. Given the cytokines in this list, it is understandable the level of impact is great because it impacts Th1 and Th2 type CD4+ T cell development.

PCR

(polymerase chain reaction) is an assay that allows one to detect the presence of a particular gene sequence.

first set rejection

1-2 wks for immunological recognition and rejection

The first human kidney transplant

1935 (Russia) patient died because of a blood type mismatch rejection was due to an immediate rejection (hyperacute rejection)

normal distribution of CD4:CD8

2-3x CD4 vs 8

On the following flow cytometric plot, what is the percentage of single positive cytotoxic T cells?

40.18%CTLs are CD8 positive T cells (represented on the X-axis). Therefore, the correct answer is 40.18%. On this histogram, CD4 cells are shown on the Y-axis and indicates there are 44.78%. Double positive cells (those expressing both CD4 and CD8) are shown at 2.39% and double-negative cells are at 12.65%.

On the following flow cytometric plot, what is the percentage of single positive T helper cells?

44.78% CTLs are CD8 positive T cells (represented on the X-axis). Therefore, the correct answer is 40.18%. On this histogram, CD4 cells are shown on the Y-axis and indicates there are 44.78%. Double positive cells (those expressing both CD4 and CD8) are shown at 2.39% and double-negative cells are at 12.65%.

Severe combined immunodeficiency disorders (SCID)

All have a defect in the T-cell compartment. Depending on the defect, may or may not impact B and/or NK cells. Generally see a low number of circulating lymphocytes and the myeloid and erythroid lineages are generally normal. Typified by recurrent infections and is often fatal early in life. The initial infections are often fungal or viral (intracellular microbes for which T cells are needed) and not usually bacterial infections where maternal passive immunoglobulins can help prevent. Treatment is often with a bone marrow transplant (BMT) depending on the genetic defect. Outside of a BMT, life can be prolonged by life in a sterile environment until treatment is available.

Grafts between genetically identical individuals (i.e. identical twins):

Are not rejected, even without immunosuppression

Immunofluorescence

As with an ELISA, antibodies can be tagged with a fluorochrome and used to detect cells in tissue (immunohistochemistry) or cells in the blood (flow cytometry). These techniques can be used to detect location, number, and general features of cells, including tumor cells.

Types of tissue grafts

Autograft Isograft Allograft Xenograft

Bruton's hypogammaglobulinemia (X-linked hypogammaglobulinemia)

B cell defect where a mutation in the B-cell tyrosine kinase (btk) gene which impacts Heavy-chain gene rearrangement. In these patients, there is no proper Ig production resulting in a lack of peripheral B cells. Treatment is typically with passive immunoglobulins (IVIG - intravenous immunoglobulin). Patients rarely survive past teenage years

Graft-versus-host disease (GvHD)

Because bone marrow has immunoreactive cells, it is possible that the bone marrow cells themselves can reject the "host" tissue ( = GvHD) Tissue transplant patients undergoing a GvHD often present with some type of pathological condition of the skin (rash), liver or gastrointestinal tract

A 26-year-old fire-fighter is brought into the emergency department with burns over most of his body. There are some areas of concern for which the healthcare team do not feel will heal properly and therefore, the patient will need a skin graft from an unrelated donor. The patient has blood type: A and his HLA typing revealed he is: HLA A11 / HLA A74; HLA B27 / HLA B15; and HLA DR3 / HLA DRw52. Below is a list of potential donors, which of the following would be the best donor for a skin graft to the burn patient?

Blood type A. HLA A11 / HLA A15; HLA B27 / HLA B15; and HLA DR3 / HLA DRw52\ Right blood type, only one class I mismatch (HLA A15 versus A74).

ELISA and Radioimmunoassays

Both of these lab techniques utilize antibodies to detect a particular antigen. Often, the antibody is tagged to a fluorochrome (ELISA) or radioactive isotope (radioimmunoassay). In so doing on can monitor antigens associated with certain tumors, including myeloma proteins from B cell tumors, oncofetal antigens (e.g. carcinoembryonic antigen and alpha fetoprotein), and prostate specific antigens (PSA). These immunoassays are not only useful for the detection of cancer cells, these assays can also be used to monitor effectiveness of a given cancer therapy. ELISA - enzyme-linked immunosorbent assay is an enzyme-based assay to detect antigen levels in serum (similar to RIA but without radioactivity). changes in cytokine levels

Prevention of graft-versus-host disease may be accomplished by targeting the following molecules (column 1). Select the description in column 2 that details how targeting the molecule in column 1 can prevent rejection.y

CD4 is the protein on T helper cells that play an important role in graft rejection, including those due to GvHD. Th1 cells (having a DTH function) express the CD4 protein, therefore, blocking CD4 or killing CD4+ T cells can reduce the T helper cell response against the transplanted tissue. CD25 is part of the interleukin 2 receptor. Blocking CD25 can effectively prevent activation of many T cells, including both Th1 and CTLs and thus, inhibit the immune response against the transplanted tissue. CD8 is a molecule expressed on cytotoxic T cells (CTLs) and they can play a role in destruction of transplanted tissue. A mAb to CD8 will likely block activation of CD8 cells and also, when the antibody binds to the CD8 protein, can cause complement mediated lysis and thus, destruction of CD8 cells. C' mediated lysis can also occur when antibodies bind to the CD25 and CD4 molecules as well (thus, not only can these antibodies block activity of the protein, destruction of cells expressing these molecules can occur as well).

AIDS is caused by a human retrovirus that primarily kills

CD4-positive T lymphocytes.

Following a bone marrow transplant, which of the following therapies will be most appropriate to inhibit T cell-mediated immunity and the development of graft-versus-host disease? Adjuvants

Cyclosporine since GVHD is primarily due to T cells, drugs like cyclosporine target IL-2/IL-2R engagement. Blocking this engagement can help prevent T cell activation and thus, prevent GVHD.

Lymphoid immunodeficiency

Defects in T cells, B cells, or both are examples of immunodeficiencies that can occur in humans. In many cases, combined deficiencies in T and B cells are the most severe, however, some types of immunodeficiencies in T cells alone can be as problematic

Autosomal mutants

Defects include those from a RAG1, RAG2 or other enzymes that prevent development of normal B and T . Defects in adenosine deaminase (ADA) functioning is significant because it is important in DNA synthesis (can also see pulmonary and neurological abnormalities so this defect is not an "immune-system only impact).

5-year-old girl has a small deletion in chromosome 22. She has impaired thymus development with significant deficiency in the number of functional T cells. The most likely etiology for these findings is

DiGeorge syndrome. The combination of a problem with the thymus and deficient functional T cells points to a thymus problem as seen in DiGeorge syndrome. While the symptoms can be SCID-like, B cells would be relatively normal (ruling out Hyper-IgM syndrome). CGD is a myeloid deficiency and in these patients, B and T cells should be normal. ADA deficiency is one cause of SCID but does not directly impact thymus development. Lastly, I don't expect you to know which genes are on chromosome #5. That information is not needed in order to answer the question.

Chronic rejection of a tissue is most associated with differences in the classical MHC class II genes between a donor and a recipient.

False

List of primary immunodeficiency disorders:

Lymphoid deficiency disorders, including combined immunodeficiencies affecting both B and T cells (often fatal outcome early in life) or those impacting T cells (depending on the defect, may see increased infections by all types of microbes, especially intracellular microbes (viruses, protozoans, and fungi). Often see decreases in overall immunoglobulin levels. B cell deficiencies where there may be lack of one isotype all the way to a complete lack of all isotypes. Patients often have recurrent bacterial infections (especially from encapsulated bacteria (e.g. Staphylococcus, Streptococcus, etc). Myeloid deficiencies are typified with some defect impacting phagocytosis resulting in increased bacterial infections.

Primary Immunodeficiency disorder categories:

Lymphoid immunodeficiency Severe combined immunodeficiency (SCID)

A major way that the immune system can distinguish self from non-self is via the expression and recognition of self

MHC

selective IgA deficiency

Many patients with a selective Ig defect, including IgA are often asymptomatic.. In the case of selective IgA deficiency, given the role of IgA in defending against infections associated with the mucous membranes, seeing recurrent respiratory and/or genitourinary infections can occur

If this is a flow cytometric plot from the blood of a 23-year-old female, would her T cell ratio be considered within the normal range?

No

Principles of Graft rejection

Principles of Graft rejection Rejection of the graft tissue is dependent on the status of the immune response to that tissue. In other words, is the reaction a primary immune response (first set rejection) or secondary immune response (second set rejection)?

Some examples of SCID diseases are

RAG1/RAG 2 genes or mutations in signaling molecules including a part of the CD3 complex OR in the gamma chain of the IL-2R family (the defect in the gamma-chain of the IL-2R is associated with X-linked SCID). Some autosomal mutations that result in T cell and/or B cell defects are mutations in RAG1, RAG2, ADA, and even with the IL-2R alpha chain (why would IL-2R alpha chain affect the immune response?).

DiGeorge syndrome

T cell defect seen in individuals who do not have a proper functioning thymus due to a congenital thymic aplasia/hypoplasia without T cells, the most severe problem occurs early in life when the individual is susceptible to several infections

PD-1 is a molecule expressed on

T cells and when it binds to the PD-1 ligand (PD-L1 or PD-L2) it causes T cells to be tolerized (suppressed). PD-1 is a checkpoint inhibitor. Many cells express the PD-1L receptors, including tumor cells.

Which of the following cytokines is produced by tumor cells to directly decrease the anti-tumor response?

TGF-beta

While CD4 T helper cells start the process of recognition, the destruction can be due to a variety of effector functions including that caused by

Th1 (DTH) cells, CTL-mediated lysis, and ADCC when antibodies are produced that recognize antigens on the graft

A 42-year-old male reported to his primary care physician for a check up. The patient has been HIV positive for 15 years and has been taking his prescribed anti-HIV medication as directed by his physician. Recently, the patient had flu-like symptoms but has since resolved. Because of the symptoms, the patient was concerned about his immune status. Flow cytometric analysis was completed (see image). What conclusions can be made about the patient's T cell numbers?

The ratio of CD4:CD8 is normal. Since the flu-like symptoms have resolved, the patient may have only had a routine infection and likely does not have anything to be concerned about at this time.

immunosuppressive treatment

Therapies that block immune cell activation (mitotic inhibitors such as cyclophosphamide or methotrexate), general immunosuppressive drugs (corticosteroids or cyclosporin A), or specific inhibitors including a few different monoclonal antibodies (mcan prove to increase the survival of transplanted tissue

What is the role of class II MHC proteins on donor cells in graft rejection? qujz

They are recognized by recipient helper T cells, which then activate cytotoxic T cells to kill donor cells. IL-2 is a cytokine that binds to the IL-2 receptor (IL-2R) and this receptor contains three molecules: the alpha, beta, and gamma chain. In this learning activity, you learned about IL-2R alpha chain (CD25) that when blocked, can inhibit T cell activation. MHC does not interact with the IL-2 molecule nor with the IL-2R.

What is the role of class II MHC proteins on donor cells in graft rejection?

They are recognized by recipient helper T cells, which then activate cytotoxic T cells to kill the donor cells.

"self-versus-non-self" recognition in grafts

When there is a mismatch, typically differences in the MHC molecules, immune cells are activated and these cells can recognize and destroy the transplanted tissue If tissue from that same donor or another donor expressing the same MHC molecules is used again in the same recipient, then a secondary immune response can occur resulting in relatively quick rejection of the transplanted tissue (i.e. the memory response)

What causes the destruction of tissue?

While CD4+ T helper cells start the process of recognition, the destruction can be due to a variety of effector functions including that caused by Th1 (DTH) cells, CTL-mediated lysis, and ADCC when antibodies are produced that recognize antigens on the graft. Interestingly, there is evidence that shows that a CD4+ cell can be directly cytotoxic as well

SCID examples (select list of High-yield disorders)

X-linked severe combined immunodeficiency Autosomal mutants

because of the mutations, cancers are:

a complex genetic disease that has a multi-step process to originate a cancer cell heterogeneous - constant changes (mutations) and evasion of host control often has a lack of antigenicity - derived from host metastatic - able to move from one location to another

Monoclonal antibodies (mAb) are often used because they can specifically target an antigen expressed by the cancer cells and then function as antibodies do

activate the complement cascade and/or antibody-dependent cellular cytotoxicity (ADCC). stimulate apoptosis (e.g. antibodies binding to the Fas protein). prevent angiogenesis (targeting key molecules involved in this process). stimulate the immune response (e.g. anti-CD3 antibodies).

Anti-SLAMF7

activates NK cell mediated tumor killing to treat multiple myeloma

antigens recognized in grafts

alloantigens and this alloreactivity is mostly due to the foreign MHC molecules serving as the alloantigens.

cancer cells are...

altered self cells express different markers abnormal growth control lack of apoptosis p53 mutations (tumor suppressor gene) malignant = invasion and metastasis

Graft recognition is what kind of reaction

an immunological reaction

antibodies whereby one can treat donor and/or graft tissue with antibodies specific for important immune system proteins

anti-CD3 (muromonab-CD3) - first mAb used to prevent rejection anti-CD25 (alpha chain of the high-affinity IL-2R) (basiliximab) experimental CTLA4-Ig (abatacept, belatacept) which is a competitive for second signal for immune system activation = anergy (suppression)

If one suspects a patient may be susceptible to a hyperacute rejection, three days prior to the transplant, one could administer anti- :

anti-Fc antibodies to remove antibodies. A hyperacute rejection is due to preformed antibodies. To prevent this from occuring, one needs to remove those antibodies from the blood. An antibody that binds to the Fc region of antibodies would temporarily clear away antibodies in the blood. Since the antibodies are already made, knocking out T cells would not be effective.

Corticosteriods

anti-inflammatory agents often one of the key immunosuppressive agents used in many allogeneic transplants and are often combined with one of the following "specific" agents

Select all choices that are correct related to individuals of blood group type AB:

are "universal recipients" of transfusions. do not have any circulating antibodies against the A and B blood type antigens. The Rh antigen (also designated as "D") is different than the AB blood group antigens. A person who is AB could be either Rh positive or negative. Since an AB individual does not have any circulating antibodies against the A and B blood type antigens, they are the universal recipients (two of the above answer choices are correct). A haplotype is a definition of the HLA (MHC) type from an individual. While two people can have the same blood type, unless they are identical twins, it is likely that their haplotypes will be the same. Individuals with type O blood are typically the "universal donors" since they don't express the A or B blood type antigens. Therefore, even if a patient/recipient of the blood has antibodies against A, B or AB, these antibodies would not bind to type O red blood cells.

primary (congenital) immunodeficiencies

arise from some type of inherited mutations. The genetic (mutation) congenital (developmental error) occur around 1:1000 to 5:1000 live births (Up-to-date, 2022) and can impact a multitude of the immune response "arms". Out of all the primary immunodeficiency disorders, IgA deficiency is the most common.

100% mhc match has what kind of rejection

around 10% in 3mos

western blot

assay that utilizes antibodies to bind to proteins (e.g. anti-HIV antibodies).

In activated T cells, CD152 (CTLA4)

begins to move to the membrane and bind CD80/86. The significance of CTLA-4 was asked in a previous module. It is an important molecule to "turn-off" the immune response.

T lymphocytes and graft rejection

by blocking the activation of CD4+ T cells, one could extend the survival of a graft that is allogenic (i.e. having some differences in the MHC molecules) combination of blocking both CD4 and CD8 cells resulted in the longest survival of the transplant blocking CD8 cells alone was not significantly different than untreated animals

How does SLAMF7 work

can activate cell killing via: 1) ADCC and the toxic molecules released by NK cell; and, 2) can activate the NK cells to kill via perforin/granzyme mediated killing

chronic rejection

can take months to years to occur not as well understood; however, the immune reaction seems to be due to differences in minor histocompatibility antigens (molecules not part of the classical MHC molecules) immunosuppressive drugs do not seem to be effective against chronic rejection

An antigen found in relatively high concentration in the plasma of normal fetuses and a high proportion of patients with progressive carcinoma of the colon is:

carcinoembryonic antigen.

how does slamf7 work

cd139 expressed on myeloma and nk cells mAbs to cd139 = activates ADCC to kill myeloma cancer cells can activate nk cells to release toxic granules (nk cells are typically activated by reduction in MHC class 1 expression and the presence of stress molecules from the target cell)

all cancers are due to mutations (more than one) and can be due to:

chemical carcinogens (e.g. nitrates, asbestos, nicotine/tar) physical carcinogens (e.g. UV light (sun), radiation) viruses [e.g. Human T cell lymphotrophic virus 1 (HTLV-1), Epstein Barr virus (EBV), Hepatitis viruses, Human papilloma viruses (HPV)]

With no therapeutic intervention, the most likely outcome for a transplanted skin graft obtained from an unrelated donor who is HLA identical to the recipient is:

chronic rejection

A 2-month-old male infant presents with persistent diarrhea, signs and symptoms of Pneumocystis jirovecii pneumonia, and an oral fungal infection with Candida albicans. His weight is in the 10th percentile. Test results for HIV are negative by polymerase chain reaction. The most likely cause of these findings is:

defective T-cell function. the microbes described are typically found when there is a defect in T cell function.

How do we prevent GvHD

destroying any residual mature T cells from the donor bone marrow graft is helpful

RIA

detailed in type 1 hypersensitivity reactions measure serum antigen levels (hormones)

A patient with an HIV viral load of 10,000 copies/mL plasma and a CD4 T cell count of 176 cells/mm3 is:

diagnosed with AIDS. The definition of AIDS is an HIV positive individual who has a CD4 cell count below 200 cells/mm3.

autograft

donor tissue is coming from the same individual who is also the recipient (essentially, self-tissue)

Which of the following provides evidence of immune evasion by tumor cells?

downregulation of MHC I molecules by tumor cells

hyperacute rejection

due to being exposed to the same tissue/antigens at least twice occurs relatively quickly after the transplant because of the pre-existing antibodies antibodies bind to the tissue antigens and cause complement activation and the resultant cell lysis can be due to being exposed to the blood of an individual expressing the same histocompatibility antigens women who have had multiple pregnancies can produce antibodies specific to the paternal antigens and in so doing, can generate antibodies that would react to the father's histocompatibility antigens

defect of DiGeorge syndrome typically originates

during the 6-10th week of fetal development and improper formation of the 3rd and 4th pharyngeal pouches cause is unknown and treatment can be achieved by a thymic graft from a fetus The thymic donor tissue tends not to show graft-versus-host disease (GvHD).y

Patients with CGD typically present with

excessive inflammation due recurrent bacterial and fungal infections. Seeing gingivitis, swollen lymph notes and susceptibility to many opportunistic infections is common along with poor antigen-presenting cell function. There are a variety of causes of CGD with 70% due to a defect in a gene on the X-chromosome with the remaining 30% due to a mutation on one of the autosomal chromosomes

Specific immunosuppression agents include

fungal metabolites antibodies whereby one can treat donor and/or graft tissue with antibodies specific for important immune system proteins

A 6-year-old male receives a bone marrow transplant from his father during treatment for acute myelogenous leukemia. Of primary concern will be the potential for development of:

graft-versus-host disease The greatest concern is the potential for stimulating GvHD given that the transplanted tissue is bone marrow. An allergic reaction and immediate type hypersensitivity are essentially, the same answer and not the correct choice.

2nd set rejection

if put same tissue on individual again = quicker response (3-6 days)

when the T cells are activated in grafts...

immunological recognition and destruction of the donor tissue can occur

X-linked hyper-IgM immunodeficiency

individuals who have a defect in CD40L-CD40 signaling that prevents proper class switching in the B cells. Without class switching, essentially, the B cells continue to express IgM (e.g. hyper-IgM). The defect in these patients is with the CD40L on T cells (= a T cell defect that primarily affects B cells).

HIV/AIDS

infects CD4+ cells, especially T cells and macrophages. In addition to binding to the CD4 protein via the viral gp120, this protein interacts with the chemokine receptors (CXCR4 or CCR5). Another HIV viral protein, gp41, plays a role in fusion of HIV to the host cell. Upon years of HIV replication in an individual and without treatment, the population of CD4+ T cells reduce and when the count gets abnormally low, the patient often presents with opportunistic infections. one of the most common 2° immunodeficiency disorders AIDS = HIV positive along with CD4 cell count <200/mm3 blood. if left untreated, results in a lack of normal Th cell function. As the CD4+ T cell counts lower, opportunistic infections occur including due to Pneumocystis jiroveci (P. carinii; fungi) pneumonia and Kaposi sarcoma (Human herpesvirus 8; HHV-8).

Severe combined immunodeficiency (SCID)

is where there is lack of functional B and T lymphocytes. These individuals often have major problems with infections, especially intracellular microbes including those caused by fungi and viruses. most common treatment is bone marrow transplantation, however, one type of SCID (ADA deficiency) has been treated with genetic engineering.

tumor infiltrating lymphocytes (TILs)

localization of immune cells, especially T cells, are found in the area of tumor growth

how do pd-1 drugs work

mAbs against PD-1 [Nivolumab (OpdivoTM) and Pembrolizumab (KeytrudaTM)] has shown to be effective in some cancers, including non-small cell lung cancer, melanoma and squamous cell carcinoma, among other cancers by removing the checkpoint inhibition and therefore, stimulating an immune response against the cancer cells.

Monoclonal antibody (mAb) treatment of cancer

mAbs received FDA approval in the 1980s and were initially used to prevent transplant rejection. anti-CD3 was one of the earliest mAbs used in such a way. Anti-CD20 [Rituximab (RituxanTM)] is currently one of the most commonly used mAbs used to treat cancer, including select patients with Non-Hodgkin's lymphoma (often a cancer of B cells). Remember that CD20 is a common marker on B cells throughout much of its developmental stages and is also found expressed on a number of malignant B cells.

Strategies for graft survival

matching the MHC is important matching class 2 more important than matching class 1 MHC

Conventional cancer therapy typically includes

mechanisms to reduce cancer cell number via surgery, radiotherapy, and/or chemotherapy

passive immunotherapy

monoclonal abs to tumor specific antigens to cause stimulation of ADCC or C' activation may also signal apoptosis - Ab binding to Fas prevent angiogenesis - tumors stimulate blood vessels to grow beyond 1mm stimulate immune response

Patients with B cell defects generally are susceptible to bacterial infections, especially those caused by encapsulated bacteria. Why?

need antibodies to assist with ADCC and opsonization to recognize and destroy encapsulated bacteria

Tumor-associated antigens (TAA)

normal proteins that are expressed inappropriately. Either these TAA are expressed only at certain times of development (classic examples are embryonic antigens expressed later in life in some tumors) or a change in levels of expression in the tumor cells compared to normal cells. Common examples of embryonic antigens (also called oncofetal antigens) are carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP).

acute rejection

occurs 2-4 weeks after the transplant and is generally due to a primary immune response Once the T-helper (Th) cell is activated, it can recruit other cells to the area, including cytotoxic T lymphocytes (CTLs) and these effector cells can destroy the foreign tissue

In summary, in order to help increase the chance of survival of a graft

one needs to match the blood type, the MHC (as many of the genes as possible) and minor histocompatibility loci.

anti-pd1

pd-1 on t cells bind to pd-l1 on tumor cells causing suppression; blocking pd-l1 enables t-cell activation

Chronic granulomatous disease (CGD)

phagocytic cells (neutrophils) are not able to produce hydrogen peroxide/reactive oxygen species (ROS) due to a defect in NADPH oxidase activity - no oxidative burse confirmed by a negative result in the nitroblue tetrazolium dye (NBT) reductase test. If an individual makes the ROS, then the dye will be reduced and turn blue Another assay similar to the NBT is the dihydrorhodamine 123 test. This fluorochrome is not fluorescent until the NADPH oxidase interacts with the fluorochrome. In a normal individual, addition of this dye to a sample will cause the red fluorescence. In a patient with a defect in NADHP oxidase, there will be no fluorescence

fungal metabolites

prevent T cell activation (block IL-2 and IL-2 receptor transcription) and blocks signaling molecules (e.g. calcineurin) needed for T cell activation; and,

alloreactivity

recognition of foreign MHC molecules as antigenic

Since tumor cells often decrease MHC class I as well as co-stimulatory molecules (e.g. B7/CD80-86) expression, the ability to activate CD4 or CD8 cells was

reduced

Which of the following is correct regarding tumor-specific antigens?

result from mutant proteins expressed by tumor cells

antigen presenting cells (APCs) in grafts

role in presenting antigens to the CD4+ T helper cells

cancers originate from

self/host-derived cells so tumors may not be recognized as foreign (variable)

Your patient is a child who has no detectable T or B cells. This immunodeficiency is most probably the result of a defect in:

stem cells originating in the bone marrow. A defect in a child with no T or B cells indicates a SCID that likely originates in the bone marrow stem cells (e.g. a RAG defect, etc.). A defect in the thymus would primarily only impact T cells, an MAC defect would impact complement mediated lysis. T and B cells should be normal in this case. A defect in T and B cell interaction would impact the ability to effectively respond to infections, but there should still be naïve B and T cells present. The germinal center is the part of the lymph nodes where there is B cell activation/proliferation. A defect here would impact B cells but T cell numbers should be relatively normal.

Graft rejection includes:

strong Th1 cell involvement DTH - delayed type hypersensitivity T helper cells (Th1) - inflammatory CTL - cytotoxic T lymphocyte (CD8+) - mediates cytotoxicity alloantigen (alloreactive) recognition of graft cells cytokine production including interleukin 2 (IL-2) and interferon gamma (IFN-gamma), together resulting in T cell proliferation and CTL activation. These activated cells and the cytokines they produce can then result in stimulating the DTH response = recruitment of macrophages and increased MHC I and II expression (= more APC activity). Tumor necrosis factor-beta (TNF-beta), another cytokine produced can be directly cytotoxic to graft cells ADCC - (antibody-dependent cellular cytotoxicity) = release of toxic components that kill graft cells

Which of the following immunosuppressive agent is used to specifically prevent T cell activation?

tacrolimus/cyclosporine --Prednisone is a corticosteroid and functions as a non-specific anti-inflammatory agent. In many allogeneic tissue transplants, prednisone (a corticosteriod) along with other more specific agents is often used to help prevent acute rejection. Some level of immunosuppression therapy is often needed when there is an allogenic transplant (especially in tissues such as skin and kidney). --Cyclosporine and tacrolimus block IL-2 or IL-2 receptor expression and therefore, are able to specifically block T cell activation. -anti-CD20 would bind to an block B cell activation.

Mechanism to help ensure graft survival

the MHC loci codes for proteins that play the biggest role in graft survival. They are the "major" histocompatibility antigens and because humans are an outbred population and the fact that the MHC genes are polymorphic, it is challenging to find two histocompatible people. Class II MHC matches are more important than class I matches and minor histocompatibility antigens also can play a role in rejection. even if one matches the MHC, a patient may still need to have some level of immunosuppression because of minor differences between donor and recipient. blood type differences are the other major factor for graft success. Blood group antigens are expressed on RBCs, epithelial cells, and endothelial cells and play a critical role in graft survival. blood type match is often the quickest rejection if not matched (Ab + C') - hyperacute rejection. data on MHC matching in 2020 indicated there are over 25,000 allele sequences (many resulting in distinct HLA proteins) recorded in an international immunogenetics database. The more MHC class II and class I matches between donor and recipient = increased survival. These matches tend to be more important for kidney and bone marrow transplants. Currently, one typically only checks the HLA-A, -B and -DR loci for matches. Interestingly, one does not have to have as many matches in liver and heart transplants. Details on the basics of the MHC were detailed in one of my lectures from FOM I and a brief review can be found here: https://ghr.nlm.nih.gov/primer/genefamily/hla. minor histocompatibility loci are the "other" genes that play a role in graft survival and this match is not as important as the MHC, but still a factor in graft survival.

interferon gamma (IFN-gamma) was shown to play a role in

the increased expression of CTLA-4, a molecule that binds to CD80-86 and sends a negative signal to the T cell. mAbs against CTLA-4

xenografts

tissue taken from a different animal species

allograft

transplantation of healthy tissue from one person to another person

anti-CD20

treats b-cell cancers (non-hodgkin's lymphoma), binds to cd20 activates c'

tumor-specific antigens (TSA)

unique molecules expressed on their surface that can allow for immune system recognition

isograft

use of identical twin's tissue

first successful kidney transplant

was in 1954 (Boston) between identical twins

secondary (acquired) immunodeficiencies

where some change in our body has an impact on the immune response. Some of the secondary immunodeficiencies include: aging which is often associated with reduced activity of our body systems, including the immune response; malignancies, especially lymphoid cancers; treatment of various diseases, including immunosuppression to help reduce the impact of autoimmune diseases or the treatments used to fight tissue graft rejection; and, certain infectious microbes.