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Transplantation immunology part 1

Transplantation immunology part 1

Presented by Rapisa Nantanee, MD.

February 5, 2021

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Transplantation immunology part 1

  1. 1. Transplantation Immunology Part I Topic Review February 5th, 2021 Rapisa Nantanee, M.D. Pediatric Allergy and Immunology Unit King Chulalongkorn Memorial Hospital
  2. 2. Outline • Definition • Introduction • General Principles • Adaptive Immune Responses to Allografts • Patterns and Mechanisms of Allograft Rejection • Prevention and Treatment of Allograft Rejection
  3. 3. Definition • Transplantation is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual. • The individual who provides the graft is called the donor, and the individual who receives the graft is called either the recipient or the host. • If the graft is placed into its normal anatomic location, the procedure is called orthotopic transplantation; if the graft is placed in a different site, the procedure is called heterotopic transplantation. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  4. 4. Definition Transplantation Donor Graft Recipient or Host
  5. 5. • Transplantation of hematopoietic stem cells (HSCs), kidneys, livers, and hearts is now common practice in clinical medicine, and transplantation of other organs such as lung and pancreas is becoming more frequent. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  6. 6. Transplantation in Thailand 729 31 91 Kidney Heart Liver Number of Transplants Number of Transplants in 2562 สมาคมปลูกถ่ายอวัยวะแห่งประเทศไทย. รายงานข้อมูลการปลูกถ่ายอวัยวะ ประจาปี พ.ศ. 2562.
  7. 7. Introduction • The immune response against grafted tissues is the major barrier to survival of transplanted tissues or organs. • Conversely, controlling this immune response is key to successful transplantation. • Led to the development of transplantation immunology A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  8. 8. General Principles • Transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant due to an adaptive immune response. • This problem was first appreciated when attempts to replace damaged skin on burn patients with skin from unrelated donors , within 1 to 2 weeks, the transplanted skin would undergo necrosis and fall off. • Peter Medawar and other investigators studied skin transplantation in animal models, established that the failure of skin grafting was caused by an inflammatory reaction, which they called rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  9. 9. • Graft rejection is the result of an adaptive immune response. • The process had characteristics of memory and specificity and was mediated by lymphocytes. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  10. 10. General Principles • Autologous graft: a graft transplanted from one individual to the same individual. • Syngeneic graft: a graft transplanted between two genetically identical individuals. • Allogeneic graft (or allograft): A graft transplanted between two genetically different individuals of the same species • Xenogeneic graft (or xenograft): a graft transplanted between individuals of different species. • The molecules that are recognized as foreign in allografts are called alloantigens, and those in xenografts are called xenoantigens. • The lymphocytes and antibodies that react with alloantigens or xenoantigens are described as being alloreactive or xenoreactive, respectively. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  11. 11. General Principles • Innate immunity • The interruption of blood supply to tissue and organs during the time between removal from a donor and placement in a host usually cause some ischemic damage. This can result in expression of damage-associated molecular patterns (DAMPs) in the graft, which simulate innate responses mediated by both host innate cells within the graft and the donor innate immune system. • Host natural killer (NK) cells can respond to the absence of syngeneic histocompatibility molecules on donor graft cells and therefore contribute to graft rejection. • These innate responses can directly cause graft injury, but they are also believed to enhance adaptive responses by activating antigen-presenting cells (APCs). A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  12. 12. Adaptive Immune Responses to Allografts • The Nature of Alloantigens • Recognition of Alloantigens by T Cells • Activation and Effector Functions of Alloreactive T Lymphocytes • Activation of Alloreactive B Cells and Production and Functions of Alloantibodies A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  13. 13. Adaptive Immune Responses to Allografts • The Nature of Alloantigens • Most of the antigens that stimulate adaptive immune responses against allografts are proteins encoded by polymorphic genes that differ among individuals. • Histocompatibility molecules A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  14. 14. A. Cells or organs transplanted between genetically identical individuals (identical twins or members of the same inbred strain of animals) are not rejected. B. Cells or organs transplanted between genetically nonidentical people or members of two different inbred strains of a species are almost always rejected. C. The offspring of a mating between two different inbred strains of animal will not reject grafts from either parent. • An (A × B) F1 animal will not reject grafts from an A or B strain animal. (This rule is violated by hematopoietic stem cell (HSC) transplantation, when NK cells in an (A × B) F1 recipient do reject HSCs from either parent.) D. A graft derived from the offspring of a mating between two different inbred strains of animal will be rejected by either parent. • A graft from an (A × B) F1 animal will be rejected by either an A or a B strain animal. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  15. 15. Adaptive Immune Responses to Allografts • The Nature of Alloantigens • Most of the antigens that stimulate adaptive immune responses against allografts are proteins encoded by polymorphic genes that differ among individuals. • Histocompatibility molecules • Polymorphic: These graft antigens differ among the individuals of a species. (other than identical twins) • Codominant expression: Every individual inherits genes encoding these molecules from both parents, and both parental alleles are expressed. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  16. 16. Adaptive Immune Responses to Allografts • The Nature of Alloantigens • The molecules responsible for strong and rapid rejection reactions are major histocompatibility complex (MHC) molecules that bind and present peptides to T cells. • Transplants of most tissues between any pair of individuals, except identical twins, will be rejected because MHC molecules are so polymorphic that no two individuals inherit the same ones. • Human MHC molecules are called human leukocyte antigens (HLAs). • In the context of human transplantation, the terms MHC and HLA are used interchangeably. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  17. 17. Adaptive Immune Responses to Allografts • The Nature of Alloantigens • The molecules responsible for strong and rapid rejection reactions are major histocompatibility complex (MHC) molecules that bind and present peptides to T cells. • Minor histocompatibility antigens: Polymorphic antigens other than MHC molecules against which the recipient may mount an immune response • Typically induce weak or slower (more gradual) rejection reactions than do MHC molecules. • The relevance of minor histocompatibility antigens in clinical solid organ transplantation is uncertain. • Play a more significant role in stimulating graft-versus-host responses after HSC transplantation. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  18. 18. Adaptive Immune Responses to Allografts • Recognition of Alloantigens by T Cells • Allogeneic MHC molecules of a graft can be presented for recognition by the recipient’s T cells in two different ways, called direct and indirect. • Direct presentation (or direct recognition) of alloantigens: T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft. • Indirect presentation (or indirect recognition): The recipient T cells recognize graft (donor) MHC molecules only in the context of the recipient’s MHC molecules. • Implying that the recipient’s MHC molecules must be presenting peptides derived from allogeneic donor MHC proteins to recipient T cells. • The initial T cell response to MHC alloantigens most likely occurs in lymph nodes draining the graft. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  19. 19. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  20. 20. Direct alloantigen recognition occurs when alloreactive T cells bind directly to an intact allogeneic MHC molecule with bound peptide on a graft (donor) dendritic cell or other APC, within lymph nodes. Recipient CD4+ or CD8+ T cells can directly recognize donor Class II or Class I MHC molecules, respectively, and will differentiate into helper T cells or CTL. The CTL will directly recognize the same donor MHC-peptide complex displayed on graft tissue cells and kill these cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  21. 21. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. Molecular basis of direct recognition of allogeneic MHC molecules. Direct recognition of allogeneic MHC molecules may be thought of as a cross-reaction in which a T cell–specific for a self MHC molecule–foreign peptide complex (A) also recognizes an allogeneic MHC molecule (B and C). Peptides that bind to MHC molecules in the graft may contribute to allorecognition (B) or they may not (C).
  22. 22. Adaptive Immune Responses to Allografts • Recognition of Alloantigens by T Cells • Direct Recognition of MHC Alloantigens on Donor Cells • T cell responses to directly presented allogeneic MHC molecules are very strong because there is a high frequency of T cells that can directly recognize any single allogeneic MHC protein. • Estimated 1% to 10% of all T cells in an individual will directly recognize and react against an allogeneic MHC molecule on a donor cell. • Direct allorecognition can generate both CD4+ and CD8+ T cells that recognize graft antigens and contribute to rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  23. 23. Adaptive Immune Responses to Allografts • There are several explanations for the high frequency of T cells that can directly recognize allogeneic MHC molecules. • Many different peptides derived from donor cellular proteins may combine with a single allogeneic MHC molecule, and each of these peptide-MHC combinations can theoretically activate a different clone of recipient T cells. • The range of peptide-MHC complexes that can activate T cells is much greater if the MHC is allogeneic. • Many of the T cells that respond to an allogeneic MHC molecule, even on first exposure, are memory T cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  24. 24. Adaptive Immune Responses to Allografts • Recognition of Alloantigens by T Cells • Indirect Recognition of Alloantigens • Donor (allogeneic) MHC molecules are captured and processed by recipient APCs, and peptides derived from the allogeneic MHC molecules are presented in association with self MHC molecules. • Like conventional foreign protein antigens • Each allogeneic MHC molecule may give rise to multiple peptides that are foreign for the host, each recognized by different clones of T cells. • Cross-presentation or cross-priming • Allorecognition by CD4+ T cells, some are indirectly recognized by CD8+ T cells. • May contribute to chronic rejection of human allografts. • CD4+ T cells from heart and liver allograft recipients recognize and are activated by peptides derived from donor MHC when presented by the patient’s own APCs. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  25. 25. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs and peptide fragments of the allogeneic MHC molecules containing polymorphic amino acid residues are bound and presented by recipient (self) MHC molecules. Donor-MHC–specific helper T cells that are generated in this way can help B cells to produce donor- MHC–specific antibodies that can damage graft cells. The helper T cells can also be activated in the graft by recipient macrophages presenting the same donor MHC- derived peptides, leading to inflammatory damage to the graft.
  26. 26. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Activation of Alloreactive T Lymphocytes • The T cell response to an organ graft may be initiated in the lymph nodes that drain the graft. • The connection between lymphatic vessels in allografts and the recipient’s lymph nodes is surgically disrupted during the process of transplantation, and it is likely reestablished by growth of new lymphatic channels in response to inflammatory stimuli produced during grafting. • Sensitization to alloantigens: Naive CD4+ and CD8+ lymphocytes that normally traffic through the lymph node encounter these alloantigens and are induced to proliferate and differentiate into effector helper T cells and cytotoxic T lymphocytes (CTLs). • The effector cells migrate back into the graft and mediate rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  27. 27. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  28. 28. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Activation of Alloreactive T Lymphocytes • Unlike naive T cells, memory T cells may not need to see antigens presented by dendritic cells in lymph nodes in order to be activated, and they may migrate directly into grafts where they can be activated by APCs or tissue cells displaying alloantigen. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  29. 29. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Activation of Alloreactive T Lymphocytes • Mixed lymphocyte reaction (MLR) • In vitro test of the response of alloreactive T cells to foreign MHC molecules • Lymphocytes from two genetically distinct individuals are mixed together in cell culture. The T cells from one individual become activated by recognition of allogeneic MHC molecules on the cells of the other. • Used clinically in the past as a predictive test of T cell–mediated graft rejection, and as an in vitro model to study the mechanisms of alloreactivity A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  30. 30. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Role of Costimulation in T Cell Responses to Alloantigens • In addition to recognition of alloantigen, costimulation of T cells primarily by B7 molecules on APCs is important for activating alloreactive T cells. • Costimulation is likely most important to activate naive alloreactive T cells, but even alloreactive memory T cell responses can be enhanced by costimulation. • One possibility is that the innate response to ischemic damage of some cells in the graft, results in increased expression of costimulators on APCs. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  31. 31. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Effector Functions of Alloreactive T Cells • Alloreactive CD4+ and CD8+ T cells that are activated by graft alloantigens cause rejection by distinct mechanisms. • The CD4+ helper T cells differentiate into cytokine-producing effector cells that damage grafts by cytokine-mediated inflammation, similar to a delayed- type hypersensitivity (DTH) reaction. • CD8+ T cells differentiate into CTLs, which kill graft cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  32. 32. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  33. 33. Adaptive Immune Responses to Allografts • Activation and Effector Functions of Alloreactive T Lymphocytes • Effector Functions of Alloreactive T Cells • Only CTLs that are generated by direct allorecognition can kill graft cells, whereas both CTLs and helper T cells generated by either direct or indirect alloantigen recognition can cause cytokine- mediated damage to grafts. • CD8+ CTLs that are generated by direct allorecognition of donor MHC molecules on donor APCs can recognize the same MHC molecules on parenchymal cells in the graft and kill those cells. These T cells can also secrete cytokines that cause damaging inflammation. • In contrast, any CD8+ CTLs that are generated in response to indirect recognition of allogeneic MHC are restricted to recognition of peptides from these allogeneic MHC molecules bound to recipient (self) MHC molecules, and therefore the T cells will not be able to kill the foreign graft cells because the graft does not express recipient MHC molecules. The principal mechanism of rejection is inflammation caused by the cytokines produced by the effector T cells. • CD4+ effector T cells are generated by direct or indirect recognition of allogeneic MHC, the principal mechanism of rejection is inflammation caused by the cytokines produced by the effector T cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  34. 34. Adaptive Immune Responses to Allografts • Activation of Alloreactive B Cells and Production and Functions of Alloantibodies • Antibodies against graft antigens, called donor-specific antibodies, also contribute to rejection. • These high-affinity alloantibodies are mostly produced by helper T cell–dependent activation of alloreactive B cells, much like antibodies against other protein antigens. • Naive B lymphocytes recognize the allogenic MHC molecules, internalize and process these proteins, and present peptides derived from them to helper T cells that were previously activated by the same peptides presented by dendritic cells. (Indirect presentation of alloantigens) • The antigens most frequently recognized by alloantibodies are donor MHC molecules, including both class I and class II MHC proteins. • Donor-specific antibodies against non-HLA alloantigens also contribute to rejection. • The same effector mechanisms that antibodies use to combat infections. • Complement activation, and Fc receptor-mediated binding and activation of neutrophils, macrophages, and NK cells. • Because MHC antigens are expressed on endothelial cells, much of the alloantibody-mediated damage is targeted at the graft vasculature. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  35. 35. Patterns and Mechanisms of Allograft Rejection • For historical reasons, graft rejection is classified on the basis of histopathologic features and the time course of rejection after transplantation rather than on the basis of immune effector mechanisms. • Hyperacute Rejection • Acute Rejection • Chronic Rejection and Graft Vasculopathy A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  36. 36. Patterns and Mechanisms of Allograft Rejection • Hyperacute Rejection • Characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens. • Complement activation leads to endothelial cell injury and exposure of subendothelial basement membrane proteins that activate platelets. • The endothelial cells are stimulated to secrete high–molecular-weight forms of von Willebrand factor, which causes platelet adhesion and aggregation. • Both endothelial cells and platelets undergo membrane vesiculation, leading to shedding of lipid particles that promote coagulation. • Endothelial cells lose the cell surface heparan sulfate proteoglycans that normally interact with antithrombin III to inhibit coagulation. • These processes contribute to thrombosis and vascular occlusion, and the grafted organ suffers irreversible ischemic necrosis. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  37. 37. Hyperacute Rejection A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  38. 38. Patterns and Mechanisms of Allograft Rejection • Hyperacute Rejection • In the early days of transplantation: preexisting IgM alloantibodies specific for the carbohydrate ABO blood group antigens that are expressed on red cells and endothelial cells. • Hyperacute rejection by anti-ABO antibodies is extremely rare now because all donor and recipient pairs have compatible ABO types. • Natural antibodies, specific for a variety of antigens that differ among species, is a major barrier to xenotransplantation. • Currently, the rare instances of hyperacute rejection of allografts are mediated by IgG antibodies directed against protein alloantigens, such as donor MHC molecules, or against less defined alloantigens expressed on vascular endothelial cells. • Such antibodies generally arise as a result of previous exposure to alloantigens through blood transfusion, previous transplantation, or multiple pregnancies. • If the level of these alloreactive antibodies is low, hyperacute rejection may develop slowly, during several days, but the onset is still earlier than that typical for acute rejection. • Patients in need of allografts are routinely screened before grafting for the presence of antibodies that bind to cells of a potential organ donor to avoid hyperacute rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  39. 39. Patterns and Mechanisms of Allograft Rejection • Hyperacute Rejection • In unusual cases in which grafts have to be done between ABO-incompatible donors and recipients, graft survival may be improved by rigorous depletion of antibodies and B cells. • Sometimes, if the graft is not rapidly rejected, it survives even in the presence of anti- graft antibody. • One possible mechanism of this resistance to hyperacute rejection is increased expression of complement regulatory proteins on graft endothelial cells, a beneficial adaptation of the tissue called accommodation. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  40. 40. Patterns and Mechanisms of Allograft Rejection • Acute Rejection • Acute rejection is a process of injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies. • Often begin several days to a few weeks after transplantation • Reflects the time needed to generate alloreactive effector T cells and antibodies in response to the graft • In current clinical practice, episodes of acute rejection may occur at much later times, even years after transplantation, if immunosuppression is reduced. • Acute Cellular Rejection (mediated by T cells) • Acute Antibody-Mediated Rejection • Both typically coexist in an organ undergoing acute rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  41. 41. Patterns and Mechanisms of Allograft Rejection • Acute Cellular Rejection • The principal mechanisms of acute cellular rejection are CTL-mediated killing of graft parenchymal cells and endothelial cells and inflammation caused by cytokines produced by helper T cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  42. 42. Acute cellular rejection On histologic examination of kidney allografts, there are infiltrates of lymphocytes and macrophages. In kidney allografts, the infiltrates may involve the tubules (called tubulitis), with associated tubular necrosis, and blood vessels (called endotheliitis), with necrosis of the walls of capillaries and small arteries. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. The helper T cells include IFN-γ– and TNF-secreting Th1 cells and IL-17– secreting Th17 cells.
  43. 43. Patterns and Mechanisms of Allograft Rejection • Acute Antibody-Mediated Rejection • Alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules, on vascular endothelial cells, leading to endothelial injury and intravascular thrombosis that results in graft destruction. • The binding of the alloantibodies to the endothelial cell surface triggers local complement activation, which causes lysis of the cells, recruitment and activation of neutrophils, and thrombus formation. • Alloantibodies may also engage Fc receptors on neutrophils and NK cells, which then kill the endothelial cells. • Alloantibody binding to the endothelial surface may directly alter endothelial function by inducing intracellular signals that enhance surface expression of proinflammatory and procoagulant molecules. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  44. 44. Acute antibody mediated rejection A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. The histologic hallmarks of acute antibody-mediated rejection of renal allografts are acute inflammation of glomeruli and peritubular capillaries with focal capillary thrombosis. Immunohistochemical identification of the C4d complement fragment in capillaries of renal allografts is used clinically as an indicator of activation of the classical complement pathway and humoral rejection (brown staining).
  45. 45. Patterns and Mechanisms of Allograft Rejection • Chronic Rejection and Graft Vasculopathy • As therapy for acute rejection has improved, the major cause of the failure of vascularized organ allografts has become chronic rejection. • Develops insidiously during months or years • May or may not be preceded by clinically recognized episodes of acute rejection • Chronic rejection of different transplanted organs is associated with distinct pathologic changes. • In the kidney and heart, chronic rejection results in vascular occlusion and interstitial fibrosis. • Lung transplants undergoing chronic rejection show thickened small airways (called bronchiolitis obliterans). • Liver transplants show fibrotic and nonfunctional bile ducts. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  46. 46. Patterns and Mechanisms of Allograft Rejection • Chronic Rejection and Graft Vasculopathy • A dominant lesion of chronic rejection in vascularized grafts is arterial occlusion as a result of the proliferation of intimal smooth muscle cells, and the grafts eventually fail mainly because of the resulting ischemic damage. • The arterial changes are called graft vasculopathy or accelerated graft arteriosclerosis. • Frequently seen in failed cardiac and renal allografts • Can develop in any vascularized organ transplant within 6 months to a year after transplantation. • The likely mechanisms are activation of alloreactive T cells and secretion of IFN-γ and other cytokines that stimulate proliferation of vascular smooth muscle cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  47. 47. Patterns and Mechanisms of Allograft Rejection • Chronic Rejection and Graft Vasculopathy • As the arterial lesions of graft arteriosclerosis progress, blood flow to the graft parenchyma is compromised, and the parenchyma is slowly replaced by nonfunctioning fibrous tissue. • The interstitial fibrosis seen in chronic rejection may also be a repair response to parenchymal cell damage caused by repeated bouts of acute antibody-mediated or cellular rejection, perioperative ischemia, toxic effects of immunosuppressive drugs, and even chronic viral infections. • Chronic rejection leads to congestive heart failure or arrhythmias in cardiac transplant patients or loss of glomerular and tubular function and renal failure in kidney transplant patients. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  48. 48. Chronic rejection A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima. Fibrosis and loss of tubules in a kidney with chronic rejection (lower left) adjacent to relatively normal kidney (upper right). The blue area shows fibrosis, and an artery with graft arteriosclerosis is present (bottom right).
  49. 49. Prevention and Treatment of Allograft Rejection • The strategies used in clinical practice and in experimental models to avoid or to delay rejection are general immunosuppression and minimizing the strength of the specific allogeneic reaction. • An important goal of transplantation research is to find ways of inducing donor-specific tolerance, which would allow grafts to survive without nonspecific immunosuppression. • Methods to Reduce the Immunogenicity of Allografts • Immunosuppression to Prevent or to Treat Allograft Rejection • Methods to Induce Donor-Specific Tolerance A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  50. 50. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Solid organs used in transplantation come from both living and deceased donors, and graft survival after transplantation varies depending on the source. • Living donors can donate one kidney, a lobe of a lung, and parts of liver, pancreas, or intestine. • Related donors will share more alleles of polymorphic genes, including MHC genes, than unrelated donors, and this will reduce the incidence and severity of rejection episodes. • Because MHC genes are inherited as linked haplotypes, there is a 25% chance that two siblings will have identical MHC genes, whereas the chance of an unrelated donor and recipient having identical MHC genes is extremely low. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  51. 51. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Solid organs used in transplantation come from both living and deceased donors, and graft survival after transplantation varies depending on the source. • Deceased donors, called cadaveric donors, are sources of any transplantable organ and the only source of organs such as hearts. • The survival of grafts from deceased donors is on average lower than from either related or unrelated living donors because • There is more ischemic damage to organs removed after death of the donor. • Grafts from unrelated donors usually express more antigens that differ from the recipient and can simulate stronger rejection responses than those from living donors. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  52. 52. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • In human transplantation, the major strategy to reduce graft immunogenicity has been to minimize alloantigenic differences between the donor and recipient. • ABO blood typing • Tissue typing: The determination of HLA alleles expressed on donor and recipient cells. • The detection of preformed antibodies in the recipient that recognize HLA and other antigens representative of the donor population; and • The detection of preformed antibodies in the recipient that bind to antigens of an identified donor’s cells, called crossmatching. • Not all of these tests are done in all types of transplantation. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  53. 53. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • To avoid hyperacute rejection, the ABO blood group antigens of the graft donor are selected to be compatible with the recipient. • Renal and cardiac transplantation • Natural IgM antibodies specific for allogeneic ABO blood group antigens will cause hyperacute rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  54. 54. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • In kidney transplantation, the larger the number of MHC alleles that are matched between the donor and recipient, the better the graft survival. • Of all class I and class II MHC loci, matching at HLA-A, HLA-B, and HLA-DR is most important for predicting survival of kidney allografts. • HLA-C is not as polymorphic as HLA-A or HLA-B, and HLA-DR and HLA-DQ are in linkage disequilibrium, so matching at the DR locus often also matches at the DQ locus. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  55. 55. Influence of MHC matching on graft survival. • Matching of MHC alleles between the donor and recipient significantly improves renal allograft survival. • The data shown are for deceased donor (cadaver) grafts. • HLA matching has less of an impact on survival of renal allografts from live donors, and some MHC alleles are more important than others in determining outcome. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  56. 56. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Possible to have 0 to 6 HLA mismatches of these three loci between the donor and recipient. • Because 2 codominantly expressed alleles are inherited for each of these HLA genes. • Zero-antigen mismatches predict the best survival of living related donor grafts, and grafts with one-antigen mismatches do slightly worse. • The survival of grafts with 2 – 6 HLA mismatches is significantly worse than that of grafts with zero- and one-antigen mismatches, even greater impact on nonliving (unrelated) donor renal allografts. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  57. 57. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Therefore, attempts are made to reduce the number of differences in HLA alleles expressed on donor and recipient cells, which will have a modest effect in reducing the chance of rejection. • HLA matching in renal transplantation is possible because • Donor kidneys can be stored for up to 72 hours before being transplanted. • Patients needing a kidney allograft can be maintained on dialysis until a well- matched organ is available. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  58. 58. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Therefore, attempts are made to reduce the number of differences in HLA alleles expressed on donor and recipient cells, which will have a modest effect in reducing the chance of rejection. • HLA matching in renal transplantation is possible because • Donor kidneys can be stored for up to 72 hours before being transplanted. • Patients needing a kidney allograft can be maintained on dialysis until a well-matched organ is available. • In hematopoietic stem cell transplantation, HLA matching is essential to reduce the risk of graft-versus-host disease (GVHD). A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  59. 59. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • In the case of heart and liver transplantation, organ preservation is more difficult, and potential recipients are often in critical condition. • HLA typing is not considered in pairing of potential donors and recipients, and the choice of donor and recipient is based on • ABO blood group matching, other measures of immunologic compatibility, and anatomic compatibility. • The paucity of heart donors, the emergent need for transplantation, and the success of immunosuppression override any benefit of reducing HLA mismatches between donor and recipient. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  60. 60. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • HLA haplotype determinations are now performed by polymerase chain reaction (PCR), replacing older serologic methods. • The actual nucleotide sequence, and therefore, the predicted amino acid sequence, can be directly determined for the MHC alleles of any cell, providing precise molecular tissue typing. • The nomenclature of HLA alleles: Each allele defined by sequence has at least a four-digit number, but some alleles require six or eight digits for precise definition. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  61. 61. HLA Typing Low Resolution
  62. 62. HLA Typing Low Resolution
  63. 63. HLA Typing High Resolution
  64. 64. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Patients in need of allografts are also tested for the presence of preformed antibodies against donor MHC molecules or other cell surface antigens. • 2 types of tests • Panel reactive antibody (PRA) test: screened for the presence of preformed antibodies reactive with allogeneic HLA molecules prevalent in the population. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  65. 65. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Panel reactive antibody (PRA) test: screened for the presence of preformed antibodies reactive with allogeneic HLA molecules prevalent in the population. • May be produced as a result of previous pregnancies, transfusions, or transplantation • Increases risk for hyperacute or acute vascular rejection • Small amounts of the patient’s serum are mixed with multiple fluorescently labeled beads coated with defined MHC molecules. Binding of the patient’s antibodies to beads is determined by flow cytometry. • The results are reported as PRA: the percentage of the MHC allele panel with which the patient’s serum reacts. • Determined on multiple occasions while a patient waits for an organ allograft. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  66. 66. Prevention and Treatment of Allograft Rejection • Methods to Reduce the Immunogenicity of Allografts • Cross-matching test: if the patient has antibodies that react specifically with that donor’s cells. • A potential donor is identified. • Mixing the recipient’s serum with the donor’s blood lymphocytes (a convenient source of cells, some of which express both class I and class II MHC proteins). • Complement-mediated cytotoxicity tests or flow cytometric assays can then be used to determine if antibodies in the recipient serum have bound to the donor cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  67. 67. Prevention and Treatment of Allograft Rejection • Immunosuppression to Prevent or to Treat Allograft Rejection • Immunosuppressive drugs that inhibit or kill T lymphocytes are the principal agents used to treat or prevent graft rejection. • Inhibitors of T Cell Signaling Pathways • Antimetabolites • Function-Blocking or Depleting Anti-Lymphocyte Antibodies • Costimulatory Blockade • Drugs Targeting Alloantibodies and Alloreactive B Cells • Antiinflammatory Drugs A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  68. 68. Mechanisms of action of immunosuppressive drugs. • Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  69. 69. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  70. 70. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  71. 71. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  72. 72. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  73. 73. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  74. 74. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  75. 75. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • The calcineurin inhibitors cyclosporine and tacrolimus (FK506) inhibit transcription of certain genes in T cells, most notably genes encoding cytokines such as IL-2. • Cyclosporine is a fungal peptide that binds with high affinity to a ubiquitous cellular protein called cyclophilin. • The complex of cyclosporine and cyclophilin binds to and inhibits the enzymatic activity of the calcium/calmodulin-activated serine/threonine phosphatase calcineurin. • Calcineurin is required to activate the transcription factor NFAT (nuclear factor of activated T cells). • Cyclosporine inhibits NFAT activation and the transcription of IL-2 and other cytokine genes. • The net result is that cyclosporine blocks the IL-2–dependent proliferation and differentiation of T cells. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  76. 76. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • The calcineurin inhibitors cyclosporine and tacrolimus (FK506) inhibit transcription of certain genes in T cells, most notably genes encoding cytokines such as IL-2. • Tacrolimus is a macrolide made by a bacterium that functions like cyclosporine. • Tacrolimus binds to FK506 binding protein (FKBP) and the complex shares with the cyclosporine-cyclophilin complex the ability to bind calcineurin and inhibit its activity. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  77. 77. Influence of cyclosporine on graft survival. • Five-year survival rates for patients receiving cardiac allografts increased significantly beginning when cyclosporine was introduced in 1983. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  78. 78. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • The calcineurin inhibitors cyclosporine and tacrolimus (FK506) • Limitations • At doses needed for optimal immunosuppression, cyclosporine causes kidney damage, and some rejection episodes are refractory to cyclosporine treatment. • Tacrolimus was initially used for liver transplant recipients, but it is now used widely for immunosuppression of kidney allograft recipients, including those who are not adequately controlled by cyclosporine. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  79. 79. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  80. 80. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  81. 81. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • The immunosuppressive drug rapamycin (sirolimus) inhibits growth factor–mediated T cell proliferation. • Rapamycin binds to FKBP, like tacrolimus, but the rapamycin-FKBP complex does not inhibit calcineurin. Instead, this complex binds to and inhibits a cellular enzyme called mammalian target of rapamycin (mTOR), which is a serine/threonine protein kinase required for translation of proteins that promote cell survival and proliferation. • mTOR is negatively regulated by a protein complex called tuberous sclerosis complex 1 (TSC1)–TSC2 complex. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  82. 82. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • The immunosuppressive drug rapamycin (sirolimus) inhibits growth factor–mediated T cell proliferation. • Phosphatidylinositol 3-kinase (PI3K)–Akt signaling results in phosphorylation of TSC2 and release of mTOR inhibition. • Several growth factor receptor signaling pathways, including the IL-2 receptor pathway in T cells, as well as TCR and CD28 signals, activate mTOR through PI3K-Akt, leading to translation of proteins needed for cell cycle progression. • By inhibiting mTOR function, rapamycin blocks T cell proliferation. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  83. 83. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • Rapamycin (sirolimus) • Inhibits the generation of effector T cells but does not impair the survival and functions of regulatory T cells (Tregs) as much, which may promote immune suppression of allograft rejection. • mTOR is involved in • Dendritic cell functions -- may suppress T cell responses by its effects on dendritic • B cell proliferation and antibody responses -- may also be effective in preventing or treating antibody-mediated rejection. • Combinations of cyclosporine (which blocks IL-2 synthesis) and rapamycin (which blocks IL-2–driven proliferation) potently inhibit T cell responses. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  84. 84. Prevention and Treatment of Allograft Rejection • Inhibitors of T Cell Signaling Pathways • Other molecules involved in cytokine and TCR signaling are also targets of immunosuppressive drugs that are in trials for treatment or prevention of allograft rejection. • One of these target molecules is the tyrosine kinase JAK3, which is involved in signaling by various cytokine receptors, including IL-2, and protein kinase C, an essential kinase in TCR signaling. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  85. 85. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  86. 86. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  87. 87. Prevention and Treatment of Allograft Rejection • Antimetabolites • Metabolic toxins that kill proliferating T cells are used in combination with other drugs to treat graft rejection. • Inhibit the proliferation of lymphocyte precursors during their maturation and also kill proliferating mature T cells that have been stimulated by alloantigens. • Azathioprine • The first drug to be developed for the prevention and treatment of rejection. • Still used, but it is toxic to precursors of leukocytes in the bone marrow and enterocytes in the gut. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  88. 88. Prevention and Treatment of Allograft Rejection • Antimetabolites • Metabolic toxins that kill proliferating T cells are used in combination with other drugs to treat graft rejection. • Mycophenolate mofetil (MMF): The most widely used drug in this class. • Metabolized to mycophenolic acid, which blocks the activity of inosine monophosphate dehydrogenase, an enzyme required for de novo synthesis of guanine nucleotides. • Because proliferating lymphocytes are particularly dependent on de novo synthesis of purines, MMF targets lymphocytes in a relatively specific manner. • MMF is now routinely used, often in combination with cyclosporine or tacrolimus to prevent acute allograft rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  89. 89. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  90. 90. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  91. 91. Post-2017 INN -mab A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016. P. Mayrhofer and R. Kunert. Human Antibodies 27 (2019) 37–51.
  92. 92. Prevention and Treatment of Allograft Rejection • Function-Blocking or Depleting Anti-Lymphocyte Antibodies • Antibodies that react with T cell surface structures and deplete or inhibit T cells are used to treat acute rejection episodes. • The first anti-T cell antibody used in transplant patients was a mouse monoclonal antibody called OKT3 that is specific for human CD3. • OKT3 was the first monoclonal antibody used as a drug in humans, but it is no longer being produced. • Anti-thymocyte globulin: Polyclonal rabbit or horse antibodies specific for a mixture of human T cell surface proteins • Treat acute allograft rejection • Deplete circulating T cells either by activating the complement system to eliminate T cells or by opsonizing them for phagocytosis. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  93. 93. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  94. 94. Prevention and Treatment of Allograft Rejection • Function-Blocking or Depleting Anti-Lymphocyte Antibodies • Monoclonal antibodies specific for CD25, the α subunit of the IL-2 receptor • Prevent T cell activation by blocking IL-2 binding to activated T cells and IL-2 signaling. • Anti-CD52 (called alemtuzumab): A cell surface protein expressed widely on most mature B and T cells whose function is not understood. • Administered just before and early after transplantation, with the hope that it may induce a prolonged state of graft tolerance as new lymphocytes develop in the presence of the allograft. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  95. 95. Prevention and Treatment of Allograft Rejection • Function-Blocking or Depleting Anti-Lymphocyte Antibodies • The major limitation to the use of monoclonal or polyclonal antibodies from other species is that • Humans given these agents produce anti-Ig antibodies that neutralize the injected foreign Ig. • Human-mouse chimeric (humanized) antibodies (e.g., against CD3 and CD25), which are less immunogenic, have been developed. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  96. 96. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  97. 97. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  98. 98. P. F. Halloran. N Engl J Med 2004;351:2715-29.
  99. 99. Prevention and Treatment of Allograft Rejection • Costimulatory Blockade • Drugs that block T cell costimulatory pathways reduce acute allograft rejection. • To prevent the delivery of costimulatory signals required for activation of T cells. • Belatacept: A high-affinity form of CTLA4-Ig • CTLA4-Ig is a recombinant protein composed of the extracellular portion of CTLA4 fused to an IgG Fc domain. • Binds to B7 molecules on APCs and prevents them from interacting with T cell CD28. • As effective as cyclosporine in preventing acute rejection, but its high cost and other factors have limited widespread use • Anti-CD40L antibody: An antibody that binds to T cell CD40 ligand (CD40L) and prevents its interactions with CD40 on APCs. • Thrombotic complications, apparently related to the expression of CD40L on platelets. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  100. 100. Prevention and Treatment of Allograft Rejection • Costimulatory Blockade • Costimulation Blockade by CD154:CD40 Targeting (Anti-CD40 mAb) • The CD154 (also known as CD40L; present on activated T cells): CD40 (on APCs) interaction is a critical step in T cell costimulatory signaling, because this interaction leads to the upregulation of CD80/86 on APCs. • A number of mAbs against CD40 are in development, with a fully human anti-CD40 (ASKP1240; Astellas) under study in phase 2 clinical trials in kidney transplantation. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  101. 101. Prevention and Treatment of Allograft Rejection • Drugs Targeting Alloantibodies and Alloreactive B Cells • Intravenous immunoglobulin (IVIG) • Pooled IgG from normal donors is injected intravenously into a patient. • The mechanisms of action are not fully understood but likely involve binding of the injected IgG to the patient’s Fc receptors on various cell types, thereby reducing alloantibody production and blocking effector functions of the patient’s own antibodies. • Enhances degradation of the patient’s antibodies by competitively inhibiting their binding to the neonatal Fc receptor. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  102. 102. Prevention and Treatment of Allograft Rejection • Drugs Targeting Alloantibodies and Alloreactive B Cells • Rituximab: An anti-CD20 antibody • B cell depletion • Approved for treatment of B cell lymphomas and for autoimmune diseases • Used in some cases of acute antibody-mediated rejection • Chimeric anti-CD20 mAb (30% murine and 70% human) • Leads to side effects attributable to cytokine release, such as fever, bronchospasm, and hypotension. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  103. 103. Prevention and Treatment of Allograft Rejection A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016. • Drugs Targeting Alloantibodies and Alloreactive B Cells • Anti-CD20 Targeting: Rituximab, Ocrelizumab, Ofatumumab, and Veltuzumab • Agents that are humanized (ocrelizumab) or fully humanized (ofatumumab) have been developed to minimize these untoward infusion reactions. • However, ocrelizumab development in RA has been discontinued because of an increased risk of serious infections. • A phase 1/2 trial of ofatumumab in RA has shown preliminary efficacy, with mild/moderate infusion reactions still prevalent. • All anti-CD20 therapy carries a risk of hepatitis B reactivation. • Therefore, before starting treatment, patients should be screened for hepatitis B surface antigen and hepatitis B core antibody.
  104. 104. Prevention and Treatment of Allograft Rejection A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016. • Drugs Targeting Alloantibodies and Alloreactive B Cells • Anti-CD22 Targeting: Epratuzumab • CD22 is expressed on B cells during B cell maturation and loss of CD20 expression. • B cell receptor signaling is modulated by phosphorylation of CD22, which regulates B cell activation. • Humanized anti-CD22 mAb that inhibits B cell activation and has a more modest depleting effect on B cells than rituximab. • It is currently in phase 3 trials in patients with moderate to severe SLE after phase 2 trials suggested a low rate of adverse events, similar to placebo
  105. 105. Prevention and Treatment of Allograft Rejection A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016. • Drugs Targeting Alloantibodies and Alloreactive B Cells • Targeting B Cell Differentiation: Belimumab and Atacicept • A key pathway for differentiation of B cells is the binding of the cytokine B cell– activating factor (BAFF; also referred to BlyS) to its B cell receptors [(BAFF-R, B cell maturation (BCMA), and transmembrane activator and CAML interactor (TACI)] and the binding of the cytokine proliferation–inducing ligand to its B cell receptors (BCMA and TACI). • Lead to increases in NF-κβ, which in turn, promote B cell differentiation and inhibit apoptosis. • Belimumab is a humanized anti-BAFF/BlyS mAb that interferes with ligand/receptor binding and inhibits this maturation. • Atacicept is a recombinant fusion protein that inhibits both BlyS and proliferation-inducing ligand.
  106. 106. Prevention and Treatment of Allograft Rejection • Drugs Targeting Alloantibodies and Alloreactive B Cells • Bortezomib: proteasome inhibitor • Kills plasma cells • Approved to treat multiple myeloma • Sometimes used to treat antibody-mediated allograft rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  107. 107. A. C. Wiseman. Clin J Am Soc Nephrol 11: 332–343, 2016.
  108. 108. Prevention and Treatment of Allograft Rejection • Antiinflammatory Drugs • Antiinflammatory agents, specifically corticosteroids, are frequently used to reduce the inflammatory reaction to organ allografts. • To block the synthesis and secretion of cytokines, including • TNF and IL-1, and other inflammatory mediators, such as prostaglandins, reactive oxygen species, and nitric oxide, produced by macrophages and other inflammatory cells. • The net result of this therapy is reduced leukocyte recruitment, inflammation, and graft damage. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  109. 109. Prevention and Treatment of Allograft Rejection • Immunosuppression to Prevent or to Treat Allograft Rejection • Current immunosuppressive protocols have dramatically improved graft survival. • Induction therapy: Strong immunosuppression is usually started in allograft recipients at the time of transplantation with a combination of drugs. • After a few days, the drugs are changed for long-term maintenance of immunosuppression. • Acute rejection is managed by rapidly intensifying immunosuppressive therapy. • Chronic rejection is more insidious than acute rejection and is much less responsive to immunosuppression than is acute rejection. • Immunosuppressive therapy leads to increased susceptibility to various types of infections and virus-associated tumors. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  110. 110. Prevention and Treatment of Allograft Rejection • Immunosuppression to Prevent or to Treat Allograft Rejection • Current immunosuppressive protocols have dramatically improved graft survival. • Immunosuppressive therapy leads to increased susceptibility to various types of infections and virus-associated tumors. • Defense against viruses and other intracellular pathogens, the physiologic function of T cells, is compromised in immunosuppressed transplant recipients. • Frequent reactivation of latent herpesviruses: CMV, HSV, VZV, EBV • Prophylactic antiviral therapy for herpesvirus infections are now given. • Greater risk for opportunistic infections • Higher risk for development of cancer • Uterine cervical carcinoma (HPV), lymphomas (EBV) • The lymphomas found in allograft recipients as a group are called post-transplantation lymphoproliferative disorders (PTLDs), and most are derived from EBV-infected B lymphocytes. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  111. 111. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Allograft rejection may be prevented by making the host tolerant to the alloantigens of the graft. • Tolerance: The host immune system does not injure the graft despite the withdrawal of immunosuppressive agents. • Alloantigen specific and will therefore avoid the major problems associated with nonspecific immunosuppression, may reduce chronic rejection. • Renal transplant patients who have received blood transfusions containing allogeneic leukocytes have a lower incidence of acute rejection episodes. • The postulated explanation for this effect is that the introduction of allogeneic leukocytes by transfusion produces tolerance to alloantigens. One underlying mechanism for tolerance induction may be that the transfused donor cells contain immature dendritic cells, which induce unresponsiveness to donor alloantigens. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  112. 112. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Several strategies are being tested to induce donor-specific tolerance in allograft recipients. • Costimulatory blockade • Hematopoietic chimerism • Transfer or induction of Tregs A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  113. 113. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Costimulatory blockade • Recognition of alloantigens in the absence of costimulation would lead to T cell tolerance. • The clinical experience is that they suppress immune responses to the allograft but do not induce long-lived tolerance, and patients have to be maintained on the therapy. • Hematopoietic chimerism • Transfer or induction of Tregs A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  114. 114. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Costimulatory blockade • Hematopoietic chimerism • Long-term allograft tolerance by hematopoietic chimerism has been achieved in a small number of renal allograft recipients who received a hematopoietic stem cell transplant from the donor at the same time as the organ allograft. • But the risks of hematopoietic stem cell transplantation and the availability of appropriate donors may limit the applicability of this approach. • Transfer or induction of Tregs A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  115. 115. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Costimulatory blockade • Hematopoietic chimerism • Transfer or induction of Tregs • Attempts to generate donor-specific Tregs in culture and to transfer these into graft recipients are ongoing. • There has been some success reported in recipients of hematopoietic stem cell transplants, in whom infusions of Tregs reduce GVHD. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  116. 116. Prevention and Treatment of Allograft Rejection • Methods to Induce Donor-Specific Tolerance • Costimulatory blockade • Hematopoietic chimerism • Transfer or induction of Tregs • Liver transplants frequently survive and function even with little or no immunosuppressive therapy. • “Operational tolerance” • It is not clear in most cases if alloreactive T cell responses are reduced or extinguished. It is also not known why the liver is unique among transplanted organs in its ability to resist rejection. A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.
  117. 117. Hematopoietic Stem Cell (HSC) Transplantation • Indications, Methods, and Immune Barriers in Hematopoietic Stem Cell Transplantation • Immunologic Complication of Hematopoietic Stem Cell Transplantation A.K. Abbas, et al. Cellular and Molecular Immunology. 9th ed. Chapter 17.

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