CH. 15

15-45 Explain how cyclosporin A acts as an immunosuppressant drug.

15-45 Cyclosporin A prevents the production of IL-2 and its high-affinity receptor, and thus prevents the activation of T cells and their proliferation and differentiation. It acts by inactivating the protein calcineurin. Calcineurin is a serine/threonine protein phosphatase that is activated by the first part of the T-cell receptor signaling pathway and dephosphorylates the transcription factor NFAT. This modification is necessary for NFAT, which normally resides in the cytoplasm, to enter the nucleus and stimulate transcription of the genes for IL-2 and the IL-2 receptor α chain. Inactivation of calcineurin by cyclosporin thus prevents the production of IL-2 and its high-affinity receptor.

15-62 In the context of organ transplantation, what is the increased risk associated with an individual's having received previous blood transfusions on multiple occasions?

15-62 There is a possibility of incompatibility between erythrocytes and leukocytes involving ABO, Rhesus antigens, HLA class I and class II molecules, and other polymorphic alloantigens. Each transfusion will stimulate alloantibody production to these polymorphic determinants, which, if present in the blood of a subsequent transfusion, will stimulate a type II hypersensitivity reaction in the recipient. Each blood transfusion increases the alloantibody pool, making it more difficult to find donors who will not cause a hypersensitivity reaction.

15-56 (A) What is a cross-match test? (B) Why is it carried out? (C) How is it carried out?

A. A cross-match test assesses the compatibility between a potential donor and a recipient for blood transfusion. B. A cross-match test is carried out to ensure that hypersensitivity reactions, such as type II hypersensitivity, do not occur as a result of antibodies in the recipient's blood reacting against blood group antigens on the donor erythrocytes, thus triggering destruction of the transfused red cells. C. To carry out a cross-match test, blood serum from the recipient (the blood fraction containing antibodies) is mixed with erythrocytes from the donor.

15-47 A. Explain how mouse monoclonal antibodies (MoAbs) can be used to suppress acute graft rejection. B. What feature of these mouse antibodies compromises their effectiveness in vivo and limits their use?

A. Anti-CD3 MoAbs are often administered to patients to suppress T-cell activity when signs of graft rejection are observed. Because CD3 is expressed only on T lymphocytes, this therapy is extremely specific. Anti-CD3 antibodies cross-link CD3:T-cell receptor complexes, leading to a reduction in the number of these complexes on the cell surface and a reduction in the number of T cells in the circulation. Suppression of effector T-cell activity protects the graft. B. Mouse MoAbs are antigenic in species other than mice and stimulate anti-MoAb responses. Repeated doses will exacerbate this situation and lead to the formation and clearance of MoAb:anti-MoAb immune complexes before the antibody can bind to the T cells, thus rendering the mouse antibody ineffective. A type III hypersensitivity reaction resembling serum sickness can also result when small immune complexes are formed; that is, when MoAb levels exceed anti-MoAb levels. Hence, repeated doses are discouraged, and physicians must restrict this form of immunosuppressive therapy to one episode of rejection.

15-44 A. Identify three general classes of drug that are used to suppress acute transplant rejection, and provide examples of each class. B. What side-effects and toxic effects are associated with each class of drug?

A. Class 1: corticosteroids. Examples: hydrocortisone and prednisone. Class 2: cytotoxic drugs. Examples: azathioprine, cyclophosphamide, and methotrexate. Class 3: T-cell activation inhibitors. Examples: cyclosporin A, tacrolimus (FK506), and rapamycin. B. Class 1: side-effects/toxic effects: fluid retention, weight gain, diabetes, bone demineralization, and thinning of the skin. Class 2: side-effects/toxic effects: nonspecifically prevent DNA replication in all mitotic cells causing, for example, diarrhea or hair loss. More specific effects are liver damage caused by azathioprine, and bladder damage caused by cyclophosphamide. Class 3: side-effects/toxic effects: nephrotoxicity and suppression of B-cell and granulocyte activation.

15-49 A. Explain why a boy with leukemia who receives a bone marrow transplant from his sister that is perfectly matched for MHC class I and class II is still likely to get graft-versus-host disease. B. Which effector T cells are usually involved in this reaction, and why?

A. Graft-versus-host disease is caused by T cells in the transplanted bone marrow making an immune response against antigens on the recipient's tissues. This can happen even though donor and recipient are HLA matched, because there are proteins other than HLA antigens that can differ between people and provoke an immune response. Such antigens are known as minor histocompatibility antigens. In a bone marrow transplant from a female to a male, the minor histocompatibility antigens most likely to cause a problem are male-specific proteins (which are encoded on the Y chromosome) that a female's T cells will not be tolerant to and will see as 'foreign' or non-self. B. CD8 cytotoxic T cells. The proteins that act as minor histocompatibility antigens are mainly intracellular proteins. Intracellular proteins of the recipient's cells are processed into peptides by proteasomes as part of normal protein degradation and turnover. These peptides are transported into the endoplasmic reticulum and thus are eventually presented on the surface of the recipient's cells by HLA class I molecules. Any peptides that are different from those in the donor may be recognized as non-self by the donor's cytotoxic T cells, which recognize peptides bound to HLA class I molecules. The naive CD8 T cells in the bone marrow can be activated to effector status by the presentation of minor histocompatibility peptides by dendritic cells in secondary lymphoid organs. Because the brother and sister share HLA class I type, the sister's T cells will be able to recognize non-self peptides presented by her brother's HLA molecules.

15-50 A. Are the criteria for selecting suitable donors the same for liver and bone marrow transplants? B. Why or why not?

A. No. B. Unlike bone marrow, in which a successful outcome is compromised by HLA mismatches, the liver can be transplanted even if there are major differences in HLA class I and class II between donor and recipient. The liver is more refractory to hyperacute or acute rejection than other vascularized organs such as the kidney; low expression levels of HLA class I and the absence of HLA class II contribute to this refractory state. Donor and recipient still need to be matched for ABO, and transplant patients receive immunosuppressive therapy to control chronic rejection.

15-42 A. Explain why an organ transplant made between a donor of blood group AB and a recipient of blood group O will always be rejected, even if it is perfectly HLA-matched and the recipient has been given immunosuppressant drugs. What is this type of rejection called? B. Give another example of ABO incompatibility between donor and recipient that would lead to this type of rejection. C. What other antigen incompatibilities, other than those of blood group, are most likely to provoke this type of rejection? D. Which pre-surgical laboratory test should be performed to prevent this type of rejection?

A. The organ would be rejected immediately by the process of hyperacute rejection as a result of the presence in the recipient's blood of preformed antibodies against the A and B blood group antigens present on the tissues of the graft. Such antibodies are made early in life as a result of exposure to common bacteria that carry surface carbohydrates similar to those on human cells. A person of blood group O would have made antibodies against bacterial 'A' and 'B' antigens, because the person does not have these antigens on their own cells and is thus not tolerant to them. These preexisting anti-A and anti-B antibodies in the recipient's blood will immediately attack the endothelium of blood vessels throughout the transplant, which expresses the A and B blood group antigens. Blood vessels become occluded through thrombus formation. The graft is deprived of oxygen and becomes engorged with blood hemorrhaging from leaky blood vessels. Hyperacute rejection occurs almost immediately after transplantation and cannot be treated once it has started. B. Other examples of combinations that will induce hyperacute rejection: O recipient, A donor; O recipient, B donor; A recipient, B donor; B recipient, A donor; A recipient, AB donor; and B recipient, AB donor. C. A recipient's preformed antibodies against an HLA class I antigen expressed on the endothelial cells of the transplant can also cause hyperacute rejection. Such antibodies can be generated in pregnancies in which the fetus expresses a paternal HLA allotype different from the maternal HLA allotype. These antibodies can also arise from HLA-incompatible blood transfusions or previous transplants. D. Hyperacute rejection can be prevented by typing and cross-matching donor and recipient for the A, B, and O blood groups and HLA antigens. The recipient's serum antibodies are assayed in vitro for their ability to bind to donor white blood cells.

15-39 Explain why, in principle, an organ transplanted from any donor other than an identical twin is almost certain to be rejected in the absence of any other treatment.

Acute rejection is due chiefly to immune responses made by the recipient's T cells against HLA class I and II molecules of the graft that are different from those of the recipient and that the recipient's immune system perceives as 'foreign.' The differences can be due to the HLA molecules, the self peptides they bind, or both. Transplantation between identical twins and transplantation of autografts are the only situations in which the graft and the recipient are genetically identical and in which there are no differences in either the HLA molecules or the bound peptides. In these situations, graft rejection does not occur. Transplantation between donors and recipients who have identical HLA class I and II molecules, usually HLA-identical siblings, almost always involves differences in the peptides that are bound by the HLA molecules. These differences trigger peptide-specific alloreactive T cells to cause graft rejection through the direct pathway of allorecognition. Although it is possible to match donor and recipient for many HLA class I and II allotypes, in practice most clinical transplants involve one or more mismatched HLA loci. For these differences in HLA type, alloreactive T-cell clones activated by either the direct or indirect pathway of allorecognition cause graft rejection. Destruction of the grafted organ is effected through a type IV delayed-type hypersensitivity response.

15-41 Contrast acute rejection and chronic rejection.

Acute rejection occurs within a few days of transplantation and is mediated by an alloreactive CD4 and CD8 T cell-mediated adaptive immune response by the recipient against the 'foreign' HLA molecules on the graft and involves the direct pathway of recognition. In contrast, chronic rejection occurs months to years after transplantation; it is mediated by anti-HLA class I and anti-HLA class II alloantibodies and involves the indirect pathway of recognition. CD4 T cells are first activated by recipient dendritic cells presenting donor-derived HLA class II allotypes of the recipient. These activated CD4 T cells in turn activate B cells, which are also presenting donor-derived allogeneic HLA peptides. This cognate interaction results in the production of anti-HLA class I (and also anti-HLA class II) antibodies.

15-55 Explain why it is necessary to match at least some of the HLA allotypes between donor and recipient in a bone marrow transplant given to remedy SCID.

After the bone marrow transplant, the patient's entire immune system, including T cells and dendritic cells, will become reconstituted from hematopoietic stem cells in the donor bone marrow. Donor-derived T cells developing in the recipient's thymus will, however, be positively selected on the recipient's HLA molecules, and will only recognize antigen in that context. If the donor and recipient do not share any HLA molecules, these T cells will not be able to recognize antigen presented by the donor-derived dendritic cells or macrophages and will not be activated in response to pathogens. Because T-cell activation is central to all adaptive immune responses, the recipient will remain severely immunodeficient and unable to make adaptive immune responses to pathogens. In addition, HLA matching reduces the severity of graft-versus-host disease (GVHD), in which mature T cells in the donor graft respond to the allogeneic MHC class I and II molecules of the recipient and attack host tissue.

15-43 We learned in Chapter 5 that the benefit of having and expressing multiple MHC class I and class II genes is that it increases the number and variety of pathogen-derived peptide antigens that can potentially be presented to T cells. If more is better, then why has natural selection not favored the evolution of more than three genes each for MHC class I and MHC class II?

Beyond a certain number of isotypes, the T-cell repertoire will be decreased, owing to the disproportionate increase in negative selection events as the number of different isotypes increases. Each additional isotype will decrease the number of T cells exported to the periphery, compromising the diversity of the T-cell population.

15-51 From a clinical perspective explain how the logistics of organ transplantation differ from those for a bone marrow transplant.

First, the medical specialists involved in carrying out the transplant and overseeing the post-transplant regimen are different for organ transplantation and for bone marrow transplantation. Patients receiving organ transplants will have transplant surgeons and physicians, whereas bone marrow recipients will consult with hematologists, oncologists, and radiologists. Second, the requirement for HLA matching and immunosuppressive therapy in organ transplantation depends on which organ is being transplanted. The success of a bone marrow transplant is much more sensitive to HLA mismatches, and the recipient's immune system is not simply immunosuppressed; rather, it is destroyed by myeloablative therapy involving chemotherapy and irradiation. Third, the pool of potential bone marrow donors is larger than the demand, unlike organ donations, for which thousands of patients are on waiting lists. Finally, the bone marrow donor is alive and healthy, whereas organ donors are on life support or have experienced a fatal accident.

15-64 Alloantibodies specific for HLA class I molecules can mediate hyperacute rejection of kidney transplants. Explain under what conditions an individual would possess preexisting antibodies against HLA class I polymorphisms.

If the individual has received a previous solid organ graft or blood transfusion that was not matched for HLA class I, a primary alloantibody response would have been mounted. Priming can also occur naturally during pregnancy when fetal cells bearing paternal HLA molecules enter the maternal circulatory system at birth. If the paternal HLA isoforms are different from the maternal isoforms, the mother will mount an anti-HLA alloantibody response. If a woman has multiple pregnancies with the same partner, her anti-HLA titer and memory B-cell population will increase. If a woman has multiple pregnancies with different partners who have disparate HLA allotypes, the diversity of anti-HLA antibody will also increase. Both scenarios restrict the number of possible donors for transplantation; unsuitable donors are eliminated from the list after cross-matching.

15-94 What explains the observation that mixed lymphocyte reactions carried out between some dizygotic twins have a negligible stimulation index?

In about 8% of dizygotic twins, the blood circulation is joined and the twins are born chimeric with hematopoietic cells of both twins present in both circulatory systems. A state of tolerance is induced to disparate major and minor histocompatibility antigens, explaining the absence of stimulation in a mixed lymphocyte reaction. These twins would also be expected to be able to donate organs or bone marrow to each other without the development of GVHD or the need for immunosuppressive drugs.

15-19 What explains the increased incidence of bone marrow graft failure and cancer relapse when mature T cells are depleted from donor bone marrow before engraftment?

Mature T-cell depletion of bone marrow reduces GVHD, but graft failure and disease recurrence in cancer patients is an associated risk with this procedure. Apparently, alloreactive T-cell responses benefit engraftment by suppressing remnants of the recipient's immune system and removing residual cancer cells through a graft-versus-leukemia (GVL) effect.

15-53 Richard French, 53 years old, was diagnosed with chronic myelogenous leukemia. His elder brother Don is HLA-haploidentical and will donate bone marrow. Richard's oncologist has recommended him to a medical center that favors using bone marrow depleted of mature T cells prior to infusion. The most likely rationale for employing the practice of T-cell depletion is that _____. a. T-cell depletion will remove alloreactive T cells from the donor and prevent the potential for graft-versus-host disease (GVHD) b. mature T-cell chimerism is required to establish long-term tolerance c. because Don is HLA-haploidentical and male, there is no risk of alloreactivity toward major or minor histocompatibility antigens d. because of Don's age, the expected bone marrow harvest is already marginal for successful engraftment, and depletion measures would compromise the yield of stem cells e. the benefit of using a cocktail of immunosuppressive drugs outweighs the risk of contaminating the bone marrow during T-cell depletion.

Rationale: The correct answer is a. An HLA haploidentical donor has one HLA haplotype in common with the recipient and one that is different. A bone marrow sample from a haploidentical donor contains numerous alloreactive T cells that can respond to the HLA class I and class II molecules encoded by the HLA class I and II genes of the recipient's HLA haplotype that is not shared with the donor. These alloreactive T cells have the potential to cause a severe and life-threatening graft-versus-host-disease. To prevent such an outcome, bone marrow grafts from haploidentical donors are purged of T cells before being infused into the recipient. Haploidentical transplants are only given to patients who are unable to find an HLA-matched donor. Family members are good candidate donors because all parents and 50% of siblings (on average) have one HLA haplotype in common and one that is different from a patient such as Richard. Unlike Don, who is HLA-haploidentical to Richard, his other sibling Margaret could not be a donor because neither of her HLA haplotypes is shared with Richard.

15-37 George Cunningham was diagnosed with Crohn's disease when 23 years old. He was experiencing acute abdominal pain, diarrhea, rectal bleeding, anemia and weight loss. He did not respond to conventional immunosuppressive therapies and was given a course of infliximab, an anti-TNF-α monoclonal antibody that suppresses inflammation by blocking TNF-α activity. On day 12 after receiving his first infusion, he developed a mild fever, generalized vasculitis, swollen lymph glands, swollen joints and joint pain. Traces of blood and protein were detected in his urine. Which of the following is the most likely cause of these recent symptoms? a. Type I hypersensitivity involving anaphylaxis. b. Type II hypersensitivity leading to hemolytic anemia. c. Type III hypersensitivity caused by immune complex deposition in blood vessels. d. Type IV hypersensitivity involving CD8 T-cell cytotoxicity. e. Type II hypersensitivity leading to thrombocytopenia.

Rationale: The correct answer is c. This is an example of serum sickness, a type III hypersensitivity reaction. George has made antibodies against infliximab, which is a chimeric monoclonal antibody made of human and mouse (foreign) components. Because this is an adaptive immune response, it takes time before sufficient levels of anti-infliximab antibody are made and cause the formation of immune complexes. Deposition of the immune complexes in blood vessels, joints, and glomeruli are causing George's symptoms. These symptoms are typically self-limiting, because as anti-infliximab antibody levels increase into the zone of antibody excess, the size of immune complexes will increase and they will then be cleared effectively by splenic macrophages, Kupffer cells of the liver, and mesangial cells of the kidney.

15-54 Forty-four-year old Danielle Bouvier is on the waiting list for a kidney transplant and is receiving weekly dialysis. Her HLA type is: HLA-A: 0101/0301; HLA-B: 0702/0801; HLA-DRB1: 0301/0701. Today, Danielle's physician informed her that several potential kidney donors are available. Which of the following would be the most suitable? a. A: 0301/0201; B: 4402/0801; DRB1: 0301/0403 b. A: 0301/2902; B: 1801/0801; DRB1: 0301/0701 c. A: 2902/0201; B: 0702/0801; DRB1: 0301/13011 d. A: 0101/0101; B: 5701/0801; DRB1: 0701/0701 e. A: 0101/0301; B: 0702/5701; DRBA: 0403/0301.

Rationale: The correct answer is d. The better the match in HLA class I and class II allotypes between the donor and the recipient, the better the outcome of the transplantation. Donor 'd' has five out of six alleles in common for HLA-A, HLA-B, and DRB. Donors 'b' and 'e' share only four, and donors 'a' and 'c' only three.

15-38 How do the clinical objectives of transplantation differ from those of vaccination?

Vaccination is used to stimulate a very specific, long-lasting immune response against a pathogen that provides protection in the event of subsequent encounter. The objective of transplantation, however, to suppress the immune response to eliminate the rejection of a graft that bears foreign epitopes.

15-16 _____ is not a drug that targets replication and proliferation of alloantigen-activated T cells. a. Rapamycin b. Methotrexate c. Mycophenolate mofetil d. Azathioprine e. Cyclophosphamide.

a

15-35 Following a hematopoietic stem cell transplant, T-cell responses will be activated by dendritic cells of _____ origin. a. donor b. recipient c. both donor and recipient.

a

15-46 Graft-versus-host disease (GVHD) is a consequence of _____. a. mature T lymphocytes from the donor mounting an immune response against tissue of the recipient b. mature T lymphocytes from the recipient mounting an immune response against tissue of the donor c. mismatching A, B, and O antigens between donor and recipient d. mismatching Rhesus antigen between donor and recipient e. antibodies of the donor stimulating NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of tissues of the recipient.

a

15-70 When donor MHC:donor self-peptide complexes activate recipient T cells, _____. a. acute rejection of transplanted organs occurs b. suppression occurs and transplanted organs are tolerated c. hyperacute rejection of transplanted organs occurs d. complement pathways are activated e. an indirect pathway of allorecognition occurs.

a

15-73 As the number of expressed MHC isoforms in the thymus increases beyond a certain value, the T-cell repertoire _____. a. becomes smaller b. becomes more diverse c. is unaffected.

a

15-77 Patients who have previously received a blood transfusion that has HLA-DR allotypes in common with their kidney transplant are _____. a. less likely to reject the graft owing to the presence of regulatory CD4 T cells b. more likely to reject the graft owing to the presence of HLA alloantibodies c. less likely to reject the graft owing to negative selection of alloreactive T-cell clones d. at risk of developing a hyperacute rejection e. at risk of developing graft-versus-host disease.

a

15-8 All of the following are commonly used sources of hematopoietic stem cells except ____. a. skin cells b. bone marrow c. umbilical cord blood d. peripheral blood.

a

15-85 Steroid receptors are complexed with _____. a. Hsp90 in the cytoplasm b. Hsp90 on the cell surface c. calcineurin in the cytoplasm d. calcineurin in the nucleus e. NFκB in the cytoplasm.

a

15-21 _____ is/are a disease or genetic defect that can be treated by bone marrow transplantation. (Select all that apply.) a. A leukocyte defect b. Multiple myeloma c. Hemoglobin defects d. Celiac disease e. Acquired immune deficiency syndrome (AIDS).

a, b, c

15-13 Which of the following is classified as a pro-drug? (Select all that apply.) a. azathioprine b. cyclophosphamide c. cyclosporin d. prednisone e. rapamycin f. mycophenolate mofetil.

a, b, d, f

15-78 The outcome of organ transplantation improves when _____. (Select all that apply.) a. the patient has been transfused with blood sharing HLA allotypes with the transplanted organ b. HLA-A, HLA-B and HLA-DR are matched c. a thymectomy is performed at the time of transplantation d. plasmapheresis is carried out before transplantation e. immunosuppressive drugs are used to prevent the activation and proliferation of T cells.

a, b, e

15-89 Which of the following human molecules would be candidates for genetic modification of pigs to make these animals more suitable as organ donors for humans? (Select all that apply.) a. membrane co-factor protein (MCP) b. decay-accelerating factor (DAF) c. HLA class II d. HLA class I e. CD59.

a, b, e

15-2 In routine blood transfusions, which of the following must be matched correctly? (Select all that apply.) a. A and B antigens b. O antigens c. Rhesus D antigen d. MHC class I molecules e. MHC class II molecules.

a, c

15-79 Which of the following are correctly matched? (Select all that apply.) a. prednisone: pro-drug b. rapamycin: calcineurin c. azathioprine: cytotoxicity d. methotrexate: NFkB e. cyclophosphamide: microbial products.

a, c

15-87 Tacrolimus causes which of the following effects? (Select all that apply.) a. reduced T-cell proliferation b. decreased production of nitric oxide c. decreased production of IL-3, IL-4, GM-CSF, and TNF-a d. decreased activity of cyclo-oxygenase type 2 e. serum sickness.

a, c

15-82 Which of the following immunosuppressive drugs functions by inhibiting DNA synthesis? (Select all that apply.) a. cyclophosphamide b. prednisone c. azathioprine d. methotrexate e. mycophenolate mofetil f. cyclosporin A g. tacrolimus.

a, c, d, e

15-7 Which of the following is a permissible match between a blood donor and a recipient (donor: recipient)? (Select all that apply.) a. O -: AB + b. O +: AB - c. AB +: O - d. A -: A + e. AB -: O +.

a, d

15-83 _____ decreases the activity of the transcription factor NFAT by inhibiting calcineurin. (Select all that apply.) a. Tacrolimus b. Azathioprine c. Mycophenolic acid d. Cyclosporin A e. Rapamycin

a, d

15-67 Which of the following are correctly matched? (Select all that apply.) a. hyperacute rejection: preexisting antibodies against cell-surface antigens b. acute rejection: anti-HLA antibodies c. chronic rejection: alloreactive T-cell clones specific for HLA allotypes of donor d. acute rejection: direct pathway of allorecognition e. transfusion effect: indirect pathway of allorecognition.

a, d, e

15-17 Which of the following exerts its effect by inhibiting the activation of calcineurin by calcium and thereby interferes with nuclear translocation of NFAT? (Select all that apply.) a. tacrolimus (FK506) b. mycophenolic acid c. cyclophosphamide d. belatacept e. cyclosporin A.

a, e

15-32 Residual leukemia cells persisting in a patient after they have received chemotherapy, irradiation, and a bone-marrow transplant are sometimes eliminated by a _____ effect which involves the action of _____. (Select all that apply.) a. graft-versus-leukemia; alloreactive T cells b. haploidentical; regulatory T cells c. acute minor histocompatibility; recipient NK cells d. myeloablation; mature T cells e. graft-versus-leukemia; alloreactive NK cells.

a, e

15-57 Match each of the following blood groups with the type(s) of blood a person with the first blood group can safely receive in a transfusion. 1. group O; 2. group A; 3. group B; 4. group AB a. group O; b. group A; c. group B, d. group AB.

a; 2—a, c; 3—a, b; 4—a, b, c, d.

15-36 Match the term in Column A with its description in Column B. Column A Column B ___a. minor histocompatibility antigens 1. allotypic differences that arise from polymorphisms in human proteins ___b. haploidentical transplant 2. on the surface of hematopoietic stem cells ___c. autologous hematopoietic cell transplantation 3. only one HLA haplotype is shared but not both ___d. graft-versus-tumor effect 4. removal of harmful cells from one's own bone marrow before reinfusion ___e. CD34 5. residual leukemic cells eliminated by alloreactive T cells or NK cells in a graft.

a—1; b—3; c—4; d—5; e—2.

15-9 Match the term in Column A with its description in Column B. Column A Column B ___a. chronic rejection 1. assessment of degree to which recipient's T cells would respond to a transplanted organ ___b. myeloablative therapy 2. annihilation of the immune system ___c. ischemia 3. a form of type III hypersensitivity ___d. mixed lymphocyte reaction 4. improved outcome of organ transplantation if previous blood transfusions containing shared HLA-DR allotypes with organ was given to recipient ___e. transfusion effect 5. blood deprivation often accompanying organ collection

a—3; b—2; c—5; d—1; e—4

15-52 Indicate whether each of the following statements is true (T) or false (F). ___a. ABO or Rhesus antigen mismatches stimulate cytotoxic T-cell responses. ___b. There are polymorphic antigens other than ABO and Rhesus antigens that can cause type II hypersensitivity reactions. ___c. Cross-matching has now been replaced with routine use of DNA-based methods. ___d. Lymphocytes and erythrocytes express HLA class I and II molecules. ___e. Platelet transfusions are used to replace fluid and prevent bleeding.

a—F; b—T; c—F; d—F; e—F

15-84 Indicate whether each of the following statements is true (T) or false (F). ___ a. Dosage of immunosuppressive drugs is often decreased in transplant patients to minimize toxic side-effects, but there is a risk of rejection. ___ b. Antithymocyte globulin (ATG) is a monoclonal antibody specific for T-cell surface antigens. ___ c. Immunosuppressive xenogeneic antibodies can be used repeatedly for multiple episodes of transplant rejection without complication. ___ d. Daclizumab, an anti-CD3 humanized antibody, is used to treat and prevent acute rejection. ___ e. A possible side-effect of using antilymphocyte globulin (ALG) is serum sickness.

a—T; b—F; c—F; d—F; e—T

15-14 All of the following culminate in complement fixation and removal of T cells by phagocytes except _____ which instead causes the T-cell receptors to be internalized and unavailable for antigen recognition. a. alemtuzumab b. OKT3 c. rabbit antithymocyte globulin (rATG).

b

15-15 In the context of allogeneic transplantation, identify the mismatched pair. a. inhibition of inflammation: prednisone b. inhibition of co-stimulation: daclizumab c. inhibition of cytokine signaling: basiliximab d. inhibition of calcineurin: tacrolimus (FK506) e. inhibition of T-cell proliferation: azathioprine.

b

15-20 _____ describes the process by which transplanted pluripotent stem cells find their way to the bone marrow spaces in the bones of the body and begin to produce new blood cells. a. Myeloablation b. Engraftment c. Relapse d. Graft-vesus-leukemia e. Chemotherapy.

b

15-25 _____ from a bone marrow transplant facilitate alloreactive responses, causing the condition defined as acute graft-versus-host disease. a. Natural killer cells b. Mature T cells c. Dendritic cells d. Thymocytes e. Mature B cells.

b

15-3 The underlying molecular basis for distinguishing blood-group antigens A, B and O is _____ at the erythrocyte surface. a. the presence or absence of fucose in glycolipids b. differences in the oligosaccharide attached to the lipid ceramide c. structural polymorphisms in the Rhesus D antigen d. the levels of MHC class I and class II molecules.

b

15-31 Males engrafted with HLA-identical bone marrow from their sisters develop graft-versus-host disease because _____. a. T cells develop in the male thymus that are not tolerant to minor histocompatibility antigens expressed by the sister b. mature T cells in the graft have specificity for male-specific minor histocompatibility antigens c. there are differences between the sexes in how self proteins are modified post-translationally d. NK-cell alloreactions occur e. residual female hormones in the graft cause upregulation of HLA class I on male dendritic cells presenting minor histocompatibility antigens.

b

15-34 What is the term used to describe the condition of an individual who possesses two sets of hematopoietic cells, one derived from the individual's own bone marrow and one derived from a different source, for example, an organ transplant or blood transfusion that has not been rejected? a. haploidentical b. chimeric c. cross-protected d. dimorphic e. mixed lymphocyte reaction.

b

15-48 Which of the following best explains why a bone marrow donor needs to be HLA-matched to the recipient? a. The bone marrow transplant contains enough mature T cells to reconstitute the recipient and the recipient provides the antigen-presenting cells. b. The recipient's MHC molecules mediate positive selection of thymocytes in the thymus that interact with donor-derived MHC molecules in the periphery. c. Reconstituted T cells are restricted by donor, not recipient, HLA allotypes. d. Without an HLA match, the donor-derived thymocytes undergo negative selection. e. If the donor is not HLA matched, the reconstituted T cells will be autoreactive.

b

15-58 What type of hypersensitivity reaction would result from a mismatched blood transfusion? a. Type I b. Type II c. Type III d. Type IV

b

15-59 What is the name of the clinical test used to determine the compatibility between a donor and recipient requiring a blood transfusion? a. desensitization b. cross-match test c. Arthus reaction d. HLA typing e. delayed-type hypersensitivity reaction

b

15-6 Alloantibodies to blood-vessel endothelium on solid organ grafts _____. a. are specific for HLA class I and class II antigens b. cause hyperacute rejection c. cause acute rejection d. target endothelium for attack by NK cells e. are IgA and do not fix complement.

b

15-61 When an individual receives a kidney transplant, the main concern will be to control the development of _____. a. graft-versus-host disease b. transplant rejection c. xenorecognition d. allergic reactions e. lymphoproliferative disorders.

b

15-69 Effector mechanisms of _____ rejection resemble those responsible for type IV hypersensitivity reactions. a. xenogeneic b. acute c. chronic d. hyperacute e. blood transfusion.

b

15-75 Alloantibody production after organ transplantation involves _____. a. a mixed lymphocyte reaction b. the indirect pathway of allorecognition by CD4 T cells c. activation of regulatory CD4 T cells d. the transfusion effect e. a switch from a chronic to an acute state of organ rejection.

b

15-30 Despite a slower engraftment, cord blood as a source of transplanted hematopoietic stem cells is better than bone marrow or than stem cells derived from peripheral blood in that _____. (Select all that apply.) a. the recipient does not need to undergo myeloablative therapy b. there is a higher degree of tolerance for HLA disparity c. there is a lower incidence of graft-versus-host disease d. cord blood can be infused directly into the bone marrow of recipients e. a larger number of stem cells express CD34.

b, c

15-26 A patient diagnosed with grade IV of graft-versus-host disease would most probably exhibit _____. (Select all that apply.) a. serum bilirubin levels of 2-3mg/dl b. jaundice c. skin blistering and desquamation d. severe abdominal pain e. maculopapular rash on less than 25% of body surface.

b, c, d

15-90 A characteristic of the human eye that enables the cornea to be transplanted with a 90% success rate is that _____. (Select all that apply.) a. antigen-presenting cells in the eye do not express the co-stimulatory molecule B7 b. the cornea is not vascularized c. anterior-chamber-associated immune deviation (ACAID) establishes a state of tolerance in the eye d. only regulatory T cells express the adhesion molecules necessary to enter the cornea e. the aqueous humor of the anterior chamber contains TGF-b, which downregulates CD40 and inhibits IL-12 secretion.

b, c, e

15-23 For the patient's new immune system to function effectively in bone marrow recipients, some HLA allotypes must be shared because _____. (Select all that apply.) a. professional antigen-presenting cells are host-derived b. professional antigen-presenting cells are donor-derived c. otherwise an autoimmune disease would develop d. newly generated T cells are positively selected on the recipient's thymic epithelium e. if all HLA molecules were mismatched, acute rejection of the grafted cells would occur.

b, d

15-5 Blood transfusions mismatched for ABO and/or rhesus antigens are associated with _____. (Select all that apply.) a. type III hypersensitivity reactions b. alloreactive immune responses c. lysis of recipient red blood cells d. laboratory errors in the cross-matching procedure e. activation of host complement and destruction of donor cells.

b, d, e

15-81 Prednisone is a steroid used in transplantation that _____. (Select all that apply.) a. binds to a cell-surface receptor and inhibits the function of NFkB b. is combined with cytotoxic drugs to improve its efficacy c. decreases the synthesis of IkBa d. causes a decrease in production of inflammatory cytokines e. can lead to bone demineralization as an unwanted side-effect.

b, d, e

15-22 Myeloablative therapy is carried out in bone marrow transplantation in order to _____. (Select all that apply.) a. prevent graft-versus-host disease b. prevent host-versus-graft disease c. suppress autoreactive T cells in the graft d. disable the patient's hematopoietic stem cells but not their circulating leukocytes e. provide space for colonization of transplanted stem cells in bone marrow stroma f. destroy tumors of immune-system cells.

b, e, f

15-10 The direct pathway of allorecognition involves interaction of _____, whereas the indirect pathway of alloreaction involves interaction of _____. a. donor T cells with allogeneic HLA molecule on recipient dendritic cells; recipient T cells with allogeneic HLA molecules on donor dendritic cells b. recipient T cells with allogeneic HLA molecules on donor dendritic cells; donor T cells with allogeneic HLA molecule on recipient dendritic cells c. recipient T cells with allogeneic HLA molecules on donor dendritic cells; recipient T cells with peptides of allogeneic HLA molecules on recipient dendritic cells d. recipient T cells with peptides of allogeneic HLA molecules on recipient dendritic cells; donor T cells with peptides of allogeneic HLA molecules on donor dendritic cells.

c

15-11 _____ is a monoclonal antibody administered to transplant patients before and after transplantation in order to induce lymphopenia. a. Rabbit antithymocyte globulin (rATG) b. Tacrolimus c. Alemtuzumab d. Belatacept e. Basiliximab.

c

15-27 Autologous bone marrow transplantation used to treat cancer patients involves reinfusing a(n) _____-depleted stem-cell population into the patient after their cancer treatment has been completed. a. mature T cell b. antibody c. tumor cell d. dendritic cell e. NK cell.

c

15-33 Family members who donate their bone marrow to a transplant patient and who share one out of the two HLA haplotypes are providing a(n) _____ transplant. a. autologous b. HLA-matched c. haploidentical d. chimeric e. cross-matched.

c

15-4 _____ results from alloreactions mediated by donor T cells in the graft subsequent to hematopoietic stem-cell transplantation. a. Acute rejection b. Chronic rejection c. Graft-versus-host disease (GVHD) d. Serum sickness e. Hyperacute rejection.

c

15-40 The term _____ is used to describe polymorphic antigens that vary between individuals of the same species. a. xenoantigens b. immunoantigens c. alloantigens d. histoantigens e. autoantigens.

c

15-68 Acute rejection of a kidney graft involves the activation of recipient T cells by _____ of _____ origin. a. dendritic cells; recipient b. B cells; recipient c. dendritic cells; donor d. macrophages; recipient e.B cells; donor.

c

15-71 The extent to which an individual's T cells respond to allogeneic HLA expressed on irradiated donor cells can be measured in vitro using _____. a. a cross-match test b. a superantigen recognition test c. the mixed lymphocyte reaction d. the transfusion effect assay e. the panel reactive antibody test.

c

15-86 Corticosteroids interfere with chemotaxis of leukocytes by _____. a. decreasing the production of GM-CSF and IL-1 b. inducing apoptosis c. inhibiting the expression of adhesion molecules on endothelial vessels d. suppressing the activity of phospholipase A2 e. reducing nitrogen oxide synthase (NOS) activity.c

c

15-88 Which of the following is an effect of both tacrolimus and corticosteroids? a. reduced T-cell proliferation b. decreased production of nitric oxide c. decreased production of IL-3, IL-4, GM-CSF, and TNF-a d. decreased activity of cyclo-oxygenase type 2 e. serum sickness.

c

15-93 What is the probability that a sibling will be able to provide a HLA-haploidentical kidney for transplantation? a. 100% b. 75% c. 50% d. 25% e. 0%.

c

15-92 Liver transplantation requires that _____ be matched between donor and recipient. (Select all that apply.) a. HLA class I b. HLA class II c. ABO antigens d. rhesus antigen.

c, d

15-60 _____ is associated with a type III hypersensitivity reaction. (Select all that apply.) a. Allergen binding to cell-surface components and creating foreign epitopes. b. Cross-linking of IgE on mast cells c. Formation of small immune complexes that are deposited in blood vessel walls d. Complement fixation e. Hemorrhaging f. Antibody excess

c, d, e

15-63 Which of the following are correctly matched? (Select all that apply.) a. allograft: same person b. autograft: to treat damage caused by autoimmune processes c. isograft: syngeneic d. antithymocyte globulin: xenogeneic e. same species: allogeneic.

c, d, e

15-91 Which of the following are transplanted with a relatively high success rate despite major differences in HLA class I and II between donor and recipient? (Select all that apply.) a. bone marrow b. heart c. cornea d. kidney e. liver.

c, e

15-18 Hematopoietic stem cell transplantation is appropriate for all of the following conditions except _____. a. thalassemia major b. Wiskott-Aldrich syndrome c. Fanconi's anemia d. cirrhosis of the liver e. sickle-cell anemia f. non-Hodgkin's lymphoma.

d

15-24 The risk of _____ is the primary complication in bone marrow transplants. a. acute host-versus-graft disease b. hyperacute rejection c. chronic rejection d. acute graft-versus-host disease e. cancer.

d

15-65 In general the higher the patient's panel reactive antibody (PRA), _____. a. the higher the number of suitable transplant donors b. the less likely it is that a hyperacute reaction will occur c. the higher the risk of developing hemolytic disease of the newborn d. the more limited the number of suitable transplant donors e. the higher the risk of developing autoimmunity.

d

15-66 If _____ occurs in an organ to be transplanted, endothelial activation, leukocyte infiltration, inflammatory cytokine production, and complement activation may occur. a. a mixed lymphocyte reaction b. the transfusion effect c. kidney dialysis d. ischemia e. myeloablative therapy.

d

15-72 In a mixed lymphocyte reaction the donor cells are irradiated to ensure that they do not _____. a. stimulate recipient cells b. become anergic c. alter their level of expression of HLA molecules d. proliferate e. undergo apoptosis.

d

15-74 In chronic rejection, effector T cells respond to _____ complexes on _____-derived dendritic cells. a. donor MHC class I:donor self peptide; donor b. donor MHC class II:donor self peptide; donor c. recipient MHC class I:donor MHC peptide; recipient d. recipient MHC class II:donor MHC peptide; recipient e. recipient MHC class II:donor MHC peptide; donor.

d

15-80 _____ is a nitrogen mustard compound converted to a DNA-alkylating agent in the body that is used to inhibit cell proliferation after transplantation. a. Methotrexate b. Rapamycin c. FK506 d. Cyclophosphamide e. Mycophenolate mofetil.

d

Vaccination is used to stimulate a very specific, long-lasting immune response against a pathogen that provides protection in the event of subsequent encounter. The objective of transplantation, however, to suppress the immune response to eliminate the rejection of a graft that bears foreign epitopes.15-1 All of the following are characteristics of blood donations and transfusions that enable their extensive use for transplantation purposes except _____. a. individuals can donate on a regular basis without any deleterious effects b. erythrocytes do not express MHC class I or class II molecules c. the blood components only need to function for a few weeks d. only the ABO antigens need to be compatible between donor and recipient e. blood transfusion is a straight forward and inexpensive process.

d

15-29 Donors treated with _____ can donate bone marrow-derived stem cells from a less invasive peripheral blood draw instead of the more invasive bone marrow aspiration. (Select all that apply.) a. anti-CD3 b. cyclophosphamide c. anti-CD34 d. granulocyte colony-stimulating factor (G-CSF) e. granulocyte-macrophage colony-stimulating factor (GM-CSF).

d, e

15-12 Which of the following is mismatched? a. methotrexate: dihydrofolate reductase b. prednisolone: NFκB c. cyclosporin: calcineurin d. basiliximab: IL-2 receptor e. OKT3: CD52 f. corticosteroid: Hsp90.

e

15-28 Leukapheresis is used in hematopoietic stem-cell transplantation where stem cells from a suitable donor are fractionated on the basis of their expression of _____. a. CD3 b. the same major histocompatibility antigens as the recipient c. the same minor histocompatibility antigens as the recipient d. the same inhibitory KIR receptors as the recipient e. CD34.

e

15-76 As time progresses following an organ transplant, the alloreactive T-cell response shifts from a(n) _____ pathway to a(n) _____ pathway of allorecognition. a. exogenous; endogenous b. inflammatory; cytotoxic c. hyperacute; suppressive d. autologous; heterologous e. direct; indirect.

e