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Transplant Immunology. Transplantation and Immunology Review of cytokines Review of cytokines Cells involved in alloreactivity Cells involved in alloreactivity.

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Presentation on theme: "Transplant Immunology. Transplantation and Immunology Review of cytokines Review of cytokines Cells involved in alloreactivity Cells involved in alloreactivity."— Presentation transcript:

1 Transplant Immunology

2 Transplantation and Immunology Review of cytokines Review of cytokines Cells involved in alloreactivity Cells involved in alloreactivity Cell to cell interaction Cell to cell interaction Major histocompatibility locus: transplant antigens Major histocompatibility locus: transplant antigens Clinical immunosuppression Clinical immunosuppression

3 Sources and Effects of Cytokines TNF MΦ, others Proliferation of T and B cells; enhances T cell function, activates MΦ and PMNs IFN-α Leukocytes Increases expression of MHC class I receptors, acute inflammatory response and macrophage activation IFN-β fibroblasts Same as IFN-α IFN-γ TH1 Activates MΦ and NK cells, Promotes TH1 pathway Upregulates MHC I/II IL-1 Proliferation of T and B cells, fever, inflammation IL-2TH1 Promotes T-cell and activated B-cell proliferation, stimulates cytokine secretion by T-cells IL-3 T cells Stimulates pluripotent stem cells IL-4TH2 Promotes TH2 differentiation B cell growth and differentiation IGE production, mast cell growth factor Inhibits secretion of proinflammatory cytokines Il-5 T-cells, mast cells Growth/differentiation of eosinophils B cell proliferation IL-6 MΦ, TH2 Induces fever, promotes B-cell maturation and differentiation, stimulates hypothalamic-pituitary-adrenal axis, induces hepatic production of acute phase proteins; levels are increased in sepsis and trauma IL-8 MΦ, endothelial cells Stimulates chemotaxis and oxidative burst by PMNs, high circulating levels associated with fatal outcome in sepsis

4 IL-9TH2 Promotes proliferation of activated T-cells IL-10TH2 Inhibits proinflammatory cytokines by MΦ IL-11 Neurons, fibroblasts, epithelial cells Increases platelet production, inhibits proliferation of enterocytes; increased levels in sepsis and DIC IL-12 MΦMΦMΦMΦ Promotes differentiation of CD4 cells to TH1 cells, enhances IFN-γ secretion by TH1 cells and NK cells; implicated in inflammatory bowel disease IL-13TH2 Inhibits proinflammatory cytokines by MΦ IL-18TH2 Costimulation of IL-12 of IFN-γ secretion by TH1 cells and NK cells

5 Cells involved in alloreactivity Key components Key components T cells T cells B cells B cells Antigen presenting cells (APC) Antigen presenting cells (APC) Development of lymphoid system begins with pluripotential stem cells in liver and bone marrow of fetus. As fetus matures, bone marrow is primary site for lymphopoiesis. Development of lymphoid system begins with pluripotential stem cells in liver and bone marrow of fetus. As fetus matures, bone marrow is primary site for lymphopoiesis. Pre T cells migrate to thymus, where CD3+ cells mature and become “educated” to self Pre T cells migrate to thymus, where CD3+ cells mature and become “educated” to self Learn to restrict to self MHC and learn tolerance to self antigens Learn to restrict to self MHC and learn tolerance to self antigens Mature T cells then populate lymph nodes, spleen, gut Mature T cells then populate lymph nodes, spleen, gut

6 Development of tolerance occurs centrally and peripherally Development of tolerance occurs centrally and peripherally Central tolerance occurs through clonal deletion in the thymus Central tolerance occurs through clonal deletion in the thymus Pre-T cells (CD3+) enter thymus, proliferate and become CD4+ and CD8+ Pre-T cells (CD3+) enter thymus, proliferate and become CD4+ and CD8+ Undergo “education” by self MHC class I or II Undergo “education” by self MHC class I or II

7 POSITIVE SELECTION POSITIVE SELECTION T cells that have a TCR receptor molecule with intermediate affinity for self MHC survive T cells that have a TCR receptor molecule with intermediate affinity for self MHC survive If affinity too high or low, cells undergo apoptosis If affinity too high or low, cells undergo apoptosis NEGATIVE SELECTION NEGATIVE SELECTION Occurs when T cells exposed to self antigens Occurs when T cells exposed to self antigens Undergo apoptosis if react too strongly Undergo apoptosis if react too strongly

8 Apoptosis Regulated cell death Regulated cell death Cell condenses, fragments, phagocytosis occurs Cell condenses, fragments, phagocytosis occurs Occurs through Fas Ligand system Occurs through Fas Ligand system Fas- receptor expressed on activated T cells Fas- receptor expressed on activated T cells Expression of Fas and FasL lead to apoptosis Expression of Fas and FasL lead to apoptosis

9 Cell to Cell Interactions APCs- dendritic cells and macrophages- APCs- dendritic cells and macrophages- Bind antigen and present it to B and T cells Bind antigen and present it to B and T cells Protein antigens need to be digested by phagocytes before presented to lymphocytes for self and non self recognition by MHC Protein antigens need to be digested by phagocytes before presented to lymphocytes for self and non self recognition by MHC

10 T cell activation TCR- T cell receptor recognizes antigens only if presented as peptide/MHC complexes presented on surface of APCs TCR- T cell receptor recognizes antigens only if presented as peptide/MHC complexes presented on surface of APCs TCR (heterodimer) binds covalently with CD3 molecule TCR (heterodimer) binds covalently with CD3 molecule Foreign antigen causes conformational change; causes intracellular signaling Foreign antigen causes conformational change; causes intracellular signaling When T cell activated, TCRs decrease; IL-2/IL-2R release increases(thru phospholipase C activation) When T cell activated, TCRs decrease; IL-2/IL-2R release increases(thru phospholipase C activation) T cell proliferates T cell proliferates

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12 T cell activation also requires co-stimulatory signals (CD 28/B-7 interaction) Without this, T cell anergy results (basis for monoclonal Ab)

13 T cell effector functions Cytotoxic T cells (CD8)- interact with MHC class I/peptide complexes and lead to cell lysis Cytotoxic T cells (CD8)- interact with MHC class I/peptide complexes and lead to cell lysis Helper T cells (CD4)- recognize antigen in context of MHC class II molecules Helper T cells (CD4)- recognize antigen in context of MHC class II molecules Leads to cell mediated (TH1) or humoral (TH2) response Leads to cell mediated (TH1) or humoral (TH2) response

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15 B lymphocytes IL-7- growth factor for pre B cells IL-7- growth factor for pre B cells IL-4, 5, 6 stimulate maturation and proliferation of B cells IL-4, 5, 6 stimulate maturation and proliferation of B cells Responsible for antibody mediated immune response against foreign antigen Responsible for antibody mediated immune response against foreign antigen Express immunoglobulin antibody on cell surface Express immunoglobulin antibody on cell surface One antigen specific antibody produced per mature B cell One antigen specific antibody produced per mature B cell Naïve B cells express IgD and IgM Naïve B cells express IgD and IgM After antigen stimulation, undergo isotype switching to produce IgG (memory B cells) After antigen stimulation, undergo isotype switching to produce IgG (memory B cells)

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17 Macrophages Role of monocyte/macrophage Role of monocyte/macrophage Phagocytosis Phagocytosis Presentation of processed antigen to lymphocytes results in production of cytokines Presentation of processed antigen to lymphocytes results in production of cytokines

18 MHC locus/transplant antigens Major histocompatibility locus located on Chromosome 6 Major histocompatibility locus located on Chromosome 6 Produces Human Leukocyte Antigens (HLA) Produces Human Leukocyte Antigens (HLA) Class I molecules are expressions of HLA-A, HLA-B, HLA-C Class I molecules are expressions of HLA-A, HLA-B, HLA-C Class II molecules are expressions of HLA-DR, HLA-DQ, HLA-DP Class II molecules are expressions of HLA-DR, HLA-DQ, HLA-DP Class III- contains mediators of immune function (TNF, heat shock protein) Class III- contains mediators of immune function (TNF, heat shock protein)

19 Comparing MHC Class I and II PropertiesClass IClass II ANTIGENSHLA-A, B, CHLA-D-DR/Q/P TISSUEOn all nucleated cells involved in DISTRIBUTION cellsimmune system FUNCTIONSEndogenous AgExogenous Ag presented to CD8presented to (cytotoxic) T-cellsCD4 (T-helpers)

20 HLA-Typing: Prevention and Rejection Must make graft less antigenic so host doesn’t reject it Must make graft less antigenic so host doesn’t reject it Major strategy: minimize alloantigen differences between donor and host Major strategy: minimize alloantigen differences between donor and host 1. ABO compatibility to prevent hyperacute rejection 2. HLA (tissue) typing: HLA-A, HLA-B, HLA-DR most important More alleles matched, greater survival of graft in 1 st year More alleles matched, greater survival of graft in 1 st year Appears to only matter if 6 allele match Appears to only matter if 6 allele match

21 HLA-typing Serologic Serologic Uses antigen specific serum to bind cells expressing antigen Uses antigen specific serum to bind cells expressing antigen Not very accurate Not very accurate Molecular Molecular PCR PCR Cross match Cross match Uses flow cytometry to test for preformed antibodies Uses flow cytometry to test for preformed antibodies

22 Rejection Three types Three types Hyperacute- due to preformed Ab Hyperacute- due to preformed Ab ABO incompatibility ABO incompatibility Minutes to hours Minutes to hours Prevented by screening Prevented by screening Result of prior pregnancy, transplant, blood transfusion Result of prior pregnancy, transplant, blood transfusion Cannot be treated with anti rejection meds Cannot be treated with anti rejection meds Mechanism- complement cascade; mediated by IgG Mechanism- complement cascade; mediated by IgG Characterized by rapid thromobosis/occlusion of graft vasculature Characterized by rapid thromobosis/occlusion of graft vasculature

23 Hyperacute Rejection

24 Acute rejection Acute rejection Mediated by T lymphocytes Mediated by T lymphocytes Occurs 1-3 weeks after transplantation without immunosuppression Occurs 1-3 weeks after transplantation without immunosuppression Most common 3-6 months post transplantation but can occur anytime Most common 3-6 months post transplantation but can occur anytime Characterized by macrophage/lymphycyte infiltration Characterized by macrophage/lymphycyte infiltration

25 Acute Rejection Two forms Two forms 1. Acute vascular rejection IgG response IgG response Leads to lysis of endothelial cells and cytokine production Leads to lysis of endothelial cells and cytokine production Endothelial necrosis Endothelial necrosis 2. Acute cellular rejection Necrosis of parenchymal cells due to infiltration of T cells and macrophages Necrosis of parenchymal cells due to infiltration of T cells and macrophages

26 Acute Rejection

27 Chronic rejection Chronic rejection Appears as fibrosis and scarring Appears as fibrosis and scarring Atherosclerosis in heart patients Atherosclerosis in heart patients BOOP in lung patients BOOP in lung patients “vanishing bile duct syndrome” in liver patients “vanishing bile duct syndrome” in liver patients Fibrosis, glomerulonephropathy in kidney patients Fibrosis, glomerulonephropathy in kidney patients Due to ischemia and inflammation Due to ischemia and inflammation

28 Chronic Rejection Risk factors Risk factors Previous acute rejection (  risk with more episodes) Previous acute rejection (  risk with more episodes) Inadequate immunosuppression Inadequate immunosuppression Initial delayed graft function Initial delayed graft function Donor factors (age, HTN) Donor factors (age, HTN) Procurement issues (ischemia time, reperfusion injury) Procurement issues (ischemia time, reperfusion injury) Recipient issues (DM, HTN, infections) Recipient issues (DM, HTN, infections)

29 Chronic Rejection

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31 Risks of immunosuppression Risks of immunosuppression Infection Infection Environmental pathogens and reactivation of host pathogens (CMV, EBV) Environmental pathogens and reactivation of host pathogens (CMV, EBV) Requires prophylaxis with gangcyclovir; hep B vaccine, Bactrim to prevent PCP, UTI Requires prophylaxis with gangcyclovir; hep B vaccine, Bactrim to prevent PCP, UTI Malignancy Malignancy No increase in lung, breast, prostate, colon, uterine CA No increase in lung, breast, prostate, colon, uterine CA Skin tumors, cervical CA, Kaposi’s, lymphoma, other virus mediated tumors more common in Tx patients Skin tumors, cervical CA, Kaposi’s, lymphoma, other virus mediated tumors more common in Tx patients Cardiovascular disease Cardiovascular disease Pretransplant risk factors (DM, HTN, CAD) amplified by immunosuppression Pretransplant risk factors (DM, HTN, CAD) amplified by immunosuppression Pts need good pre-op workup Pts need good pre-op workup Clinical immunosuppression

32 Objectives of Immunosuppression Facilitate acceptance of the allograft Facilitate acceptance of the allograft Specific Specific Low toxicity Low toxicity

33 Basic Strategies of Immunosuppression Induction (High dose initial immunosuppression) Induction (High dose initial immunosuppression) Facilitate graft acceptance Facilitate graft acceptance Minimize early rejection Minimize early rejection Favor induction of tolerance Favor induction of tolerance Maintenance therapy for chronic acceptance Maintenance therapy for chronic acceptance Augmentation to reverse acute rejection. Augmentation to reverse acute rejection.

34 Graft Rejection Highly dependent on T cell activation and proliferation. Highly dependent on T cell activation and proliferation. Signaling pathways and control points for entry into cell cycle are appropriate targets for immunsuppression. Signaling pathways and control points for entry into cell cycle are appropriate targets for immunsuppression.

35 Broad Mechanisms of Immunosuppression T cell depletion. (induction) T cell depletion. (induction) Inhibition of T cell activation. Inhibition of T cell activation. Block antigen binding. Block antigen binding. Block accessory molecules. Block accessory molecules. Inhibition of IL-2 production. Inhibition of IL-2 production. Inhibition of T cell proliferation. Inhibition of T cell proliferation. Inhibition of B cell proliferation. Inhibition of B cell proliferation.

36 Induction Agents- Thymoglobulin Antithymocyte globulin- polyclonal sera produced when human lymphocytes injected into animals (rabbit or horse) Antithymocyte globulin- polyclonal sera produced when human lymphocytes injected into animals (rabbit or horse) Interferes with cell-mediated reactions: allograft rejection, graft v host disease Interferes with cell-mediated reactions: allograft rejection, graft v host disease Used in early post transplant period or to reverse ongoing rejection Used in early post transplant period or to reverse ongoing rejection Can cause anemia, thrombocytopenia Can cause anemia, thrombocytopenia Allergic reaction most common problem Allergic reaction most common problem

37 Induction Agents- Monoclonal Antibody OKT3- engages CD3 TCR receptor OKT3- engages CD3 TCR receptor TCR receptor internalized by cell and no longer expressed on cell surface TCR receptor internalized by cell and no longer expressed on cell surface T cells removed by spleen and reticuloendothelial cells T cells removed by spleen and reticuloendothelial cells Less effective over time Less effective over time Cytokine release syndrome Cytokine release syndrome

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39 Induction Agents- IL-2R inhibitors Basiliximab/ daclizumab (CD25 Ab) Basiliximab/ daclizumab (CD25 Ab) Bind to IL-2 receptors without activating them Bind to IL-2 receptors without activating them Cells can’t bind IL-2; can’t proliferate Cells can’t bind IL-2; can’t proliferate Must be combined with other immunosuppressants Must be combined with other immunosuppressants Well tolerated Well tolerated

40 Induction Agents- Rituximab- Anti-CD 20 Ab Rituximab- Anti-CD 20 Ab Treats humoral rejection due to B cell depleting ability Treats humoral rejection due to B cell depleting ability Campath 1H- Anti CD52 Ab Campath 1H- Anti CD52 Ab Acts against B/T cells, macrophages Acts against B/T cells, macrophages Depletes lymphocytes for 2-6 months Depletes lymphocytes for 2-6 months

41 Maintenance Agents Adrenal Corticosteroid- prednisone Adrenal Corticosteroid- prednisone Antiproliferative Antiproliferative Azathioprine Azathioprine Mycophenolate mofetil Mycophenolate mofetil Leflunomide Leflunomide T cell directed T cell directed Calcineurin inhibitors: cyclosporine, tacrolimus Calcineurin inhibitors: cyclosporine, tacrolimus Cell cycle arrest: sirolimus Cell cycle arrest: sirolimus Lymphocyte Sequestration- FTY720 Lymphocyte Sequestration- FTY720

42 Adrenal Corticosteroids Suppresses transcription and secretion of IL-1, IL-6, TNF Suppresses transcription and secretion of IL-1, IL-6, TNF Inhibits IL-2 production and binding of IL-2R Inhibits IL-2 production and binding of IL-2R Blocks ability of macrophages to respond to signals such as migration inhibition and activation factors Blocks ability of macrophages to respond to signals such as migration inhibition and activation factors Side effects Side effects Cushingoid features Cushingoid features Ulcer/GI bleed Ulcer/GI bleed Diabetes Diabetes Avascular necrosis Avascular necrosis

43 Antiproliferative Agents Antimetabolites Lymphocytes depend on de novo purine synthesis rather than salvage pathway Lymphocytes depend on de novo purine synthesis rather than salvage pathway Azathioprine (6 mercaptopurine) Azathioprine (6 mercaptopurine) Blocks de novo purine synthesis, impedes T cell replication Blocks de novo purine synthesis, impedes T cell replication Mycophenolate (Cellcept) Mycophenolate (Cellcept) Blocks inosine monophosphate dehydrogenase (Rate limiting step for de novo sythesis) Blocks inosine monophosphate dehydrogenase (Rate limiting step for de novo sythesis) Side effects- diarrhea, vomiting, bone marrow suppression, opportunitistic infections Side effects- diarrhea, vomiting, bone marrow suppression, opportunitistic infections

44 Antiproliferative Agents Antimetabolites Leflunomide Leflunomide Blocks dihydro-orotate dehydrogenase (necessary for de novo pyrimidine synthesis) Blocks dihydro-orotate dehydrogenase (necessary for de novo pyrimidine synthesis)

45 Inhibitors of T cell Receptor Signaling Cyclosporine-binds to cyclophilin Cyclosporine-binds to cyclophilin Complex binds/inhibits calcineurin Complex binds/inhibits calcineurin Blocks cytokine production, esp IL-2, but does not inhibit proliferation Blocks cytokine production, esp IL-2, but does not inhibit proliferation P 450 metabolism P 450 metabolism Side Effects Side Effects Gingival Hyperplasia Gingival Hyperplasia Infection Infection Nephrotoxicity Nephrotoxicity Hypertension Hypertension Tremors, Nightmares, Insomnia Tremors, Nightmares, Insomnia Hirsutism Hirsutism Fibrous Breast Tissue Fibrous Breast Tissue

46 Inhibitors of T cell Receptor Signaling Tacrolimus (FK506, Prograf) Tacrolimus (FK506, Prograf) Also inhibits calcineurin, thus inhibiting IL-2 production Also inhibits calcineurin, thus inhibiting IL-2 production Inhibits production of cytotoxic T cells Inhibits production of cytotoxic T cells Side effects: alopecia, risk of post transplant diabetes Side effects: alopecia, risk of post transplant diabetes

47 Inhibitors of T cell Receptor Signaling Sirolimus Sirolimus Macrolide antibiotic Macrolide antibiotic Causes cell cycle arrest Causes cell cycle arrest Blocks transduction of signals from IL-2R to nucleus rather than blocking cytokine gene expression Blocks transduction of signals from IL-2R to nucleus rather than blocking cytokine gene expression

48 T cell Receptor Signaling Pathway

49 T cell Signaling: Calcineurin Calcineurin

50 Lymphocyte Sequestration FTY720 FTY720 Sequesters lymphocytes in Peyer’s patches Sequesters lymphocytes in Peyer’s patches Can cause bradycardia Can cause bradycardia

51 Treatment of Acute Rejection Need prompt diagnosis from biopsy Need prompt diagnosis from biopsy Treat mild rejection with steroids Treat mild rejection with steroids Thymoglobulin or OKT3 for severe rejection Thymoglobulin or OKT3 for severe rejection CMV prophylaxis during treatment of acute rejection CMV prophylaxis during treatment of acute rejection

52 Now for a Quick Review:

53 The correct terminology for a graft between genetically nonidentical members of the same species is: A. Allogeneic graft B. Autogeneic graft C. Isogeneic graft D. Syngeneic graft E. Xenogeneic graft

54 Which of the following statements correctly characterize the genetic basis of histocompatibility? A. Histocompatibility is determined by a series of genes inherited as a complex and subject to the mendelian rules that characterize recessive traits A. Histocompatibility is determined by a series of genes inherited as a complex and subject to the mendelian rules that characterize recessive traits B. Histocompatibility depeds in part on the inheritance of histocompatibility genes and in part of the inheritance of T-cell receptor genes B. Histocompatibility depeds in part on the inheritance of histocompatibility genes and in part of the inheritance of T-cell receptor genes C. Major histocompatibility genes are polymorphic C. Major histocompatibility genes are polymorphic D. Major histocompatibility genes are independently segregating and co-dominant D. Major histocompatibility genes are independently segregating and co-dominant E. Histocompatibility is learned E. Histocompatibility is learned

55 Which of the following distinguish MHC classs I from MHC class II antigens? A. MHC class I and class II antigens are encoded in different regions of the MHC complex A. MHC class I and class II antigens are encoded in different regions of the MHC complex B. MHC class I antigens are expressed on specialized antigen presenting cells, whereas MHC class II antigens are expressed on all cells B. MHC class I antigens are expressed on specialized antigen presenting cells, whereas MHC class II antigens are expressed on all cells C. MHC class I and class II are members of different supergene families C. MHC class I and class II are members of different supergene families D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the minor antigens D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the minor antigens MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized by the CD4 glycoprotein MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized by the CD4 glycoprotein

56 Which of the following characterize the role of the major histocompatibility antigens in immune responses? A. The major histocompatibility antigens are critical in antigen processing and presentation A. The major histocompatibility antigens are critical in antigen processing and presentation B. Major histocompatibilty antigens contribute to the maturation of T cells in the thymus B. Major histocompatibilty antigens contribute to the maturation of T cells in the thymus C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigens C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigens D. Expression of major histocompatiblity antigens is increased in inflammation D. Expression of major histocompatiblity antigens is increased in inflammation E. Recognition of major histocompatibility antigens is critical to the development of tolerance E. Recognition of major histocompatibility antigens is critical to the development of tolerance

57 Which of the following statements correctly characterize the role of histocompatibility typing in transplantation? A. Histocompatibility typing must be carried out before transplantation can be safely undertaken. A. Histocompatibility typing must be carried out before transplantation can be safely undertaken. B. The “rules” of histocompatibility wre established shrotly after the advent of immunosuppressive therapy made transplantation feasible B. The “rules” of histocompatibility wre established shrotly after the advent of immunosuppressive therapy made transplantation feasible C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typing C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typing D. The role of histocompatibility matching in transplantation is controversial D. The role of histocompatibility matching in transplantation is controversial E. The cross match test is carried out to determine whether a potential graft recipient has antibodies against the donor E. The cross match test is carried out to determine whether a potential graft recipient has antibodies against the donor

58 Activation of T cells requires: A. Stimulation of the antigen receptor A. Stimulation of the antigen receptor B. Stimulation of the MHC antigen B. Stimulation of the MHC antigen C. Co-stimulation (CD28/B7) C. Co-stimulation (CD28/B7) D. Anergy D. Anergy E. CD3 E. CD3

59 Which of the following statements characterize the biology of allotransplantation? A. The rejection response is systemic A. The rejection response is systemic B. The rejection response is learned B. The rejection response is learned C. The rejection response involves a constellation of immunologic and enviromental factors C. The rejection response involves a constellation of immunologic and enviromental factors D. Allotransplantation evokes a cellular immune response D. Allotransplantation evokes a cellular immune response E. Allotransplantation evokes a humoral immune response E. Allotransplantation evokes a humoral immune response

60 Allograft rejection may involve which of the following? A. Helper T cells A. Helper T cells B. Veto cells B. Veto cells C. Cytotoxicity C. Cytotoxicity D. Cytokines D. Cytokines E. The Arthus reaction E. The Arthus reaction

61 Which of the following statements about allograft rejection are true? A. In the absence of immunosuppression, the time and intensity of rejection of transplants between unrelated donors and recipients is highly variable. A. In the absence of immunosuppression, the time and intensity of rejection of transplants between unrelated donors and recipients is highly variable. B. Allograft rejection may be mediated by antibodies or by cells B. Allograft rejection may be mediated by antibodies or by cells C. Allograft rejection is thought to be caused by Th2 cells C. Allograft rejection is thought to be caused by Th2 cells D. Acute cellular rejection is the major cause for loss of clinical organ transplants D. Acute cellular rejection is the major cause for loss of clinical organ transplants E. An individual with “tolerance” is unable to reject an allograft E. An individual with “tolerance” is unable to reject an allograft

62 The presence of donor reactive lymphocytotoxic antiboies in the serum of a potential kidney transplant recipient: A. Can be detected by in vitro testing with recipient leukocytes and donor serum A. Can be detected by in vitro testing with recipient leukocytes and donor serum B. Is a contraindication of kidney transplantation B. Is a contraindication of kidney transplantation C. Can be found in all male patients older than 20 years C. Can be found in all male patients older than 20 years

63 Utilization of a living related donor instead of a cadaver donor is no longer an advantage in rental transplantation beause: A. Public recognition of transplantation as a successful therapy has facilitated obtaining family permission of recovery of transplantable organs. Thus, there is no need to use related donors. A. Public recognition of transplantation as a successful therapy has facilitated obtaining family permission of recovery of transplantable organs. Thus, there is no need to use related donors. B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is now comparable to related-donor transplants B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is now comparable to related-donor transplants C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many hours, consistently allowing their function to be as good as that of kidneys from living donors C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many hours, consistently allowing their function to be as good as that of kidneys from living donors D. None of the above D. None of the above

64 As compared with the early immunosuppressive drugs (azathioprine, steriods, antilyphocyte serum), some newer agents have the following specific advantages: A. Cyclosporine, which interferes with lymphokine production, exhibits neither bone marrow nor renal toxicity A. Cyclosporine, which interferes with lymphokine production, exhibits neither bone marrow nor renal toxicity B. Monoclonal antibody (OKT3) is more available and has greater specificity and few side effects than antilymphocyte serum B. Monoclonal antibody (OKT3) is more available and has greater specificity and few side effects than antilymphocyte serum C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is especially valuable for rescue of grafts that are failing on cyclosporine therapy C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is especially valuable for rescue of grafts that are failing on cyclosporine therapy D. None of the above D. None of the above

65 Which of the following statements about posttransplantation malignancy is correct? A. Certain immunosuppressive agents increase the incidence of malignancy whereas others do not A. Certain immunosuppressive agents increase the incidence of malignancy whereas others do not B. Those malignancies most commonly seen in the general population (breast, colon) are substantially more common in transplant recipients B. Those malignancies most commonly seen in the general population (breast, colon) are substantially more common in transplant recipients C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-Barr virus C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-Barr virus D. None of the above D. None of the above


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