transplantation | Anatomy2Medicine
Transplantation Types

transplantation

    • Rejection of Tissue Transplants
      • T Cell–Mediated Reactions
        • involves destruction of graft cells by
          • CD8+ CTLs
          • delayed hypersensitivity reactions triggered by activated CD4+ helper cells. (MCQ)
        • The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in highly polymorphic HLA alleles. (MCQ)
  • The recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways, called direct and indirect
        • direct pathway is the major pathway in acute cellular rejection,
        • indirect pathway is more important in chronic rejection
      • In the direct pathway(APCs in the graft initiate)
        • T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of APCs in the graft. (MCQ)
        • dendritic cells carried in the donor organs are the most important APCs for initiating the antigraft response, because they not only express high levels of class I and II MHC molecules but also are endowed with costimulatory molecules (e.g., B7-1 and B7-2). (MCQ)
        • CD8+ T cells recognize class I MHC mdecules and differentiate into active CTLs, which can kill the graft cells (MCQ)
        • CD4+ helper T cells recognize allogeneic class II molecules and proliferate and differentiate into TH1 (and possibly TH17) effector cells. (MCQ)
        • Cytokines secreted by the activated CD4+ T cells trigger a delayed hypersensitivity reaction in the graft
      • In the indirect pathway of allorecognition (recipient’s own APCs initiate)
        • recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the recipient’s own APCs.
    • Antibody-Mediated Reactions
  • Hyperacute rejection
      • occurs when preformed antidonor antibodies are present in the circulation of the recipient. (MCQ)
      • Such antibodies may be present in a recipient
        • who has previously rejected a kidney transplant.
        • Multiparous women who develop anti-HLA antibodies against paternal antigens shed from the fetus may have preformed antibodies to grafts taken from their husbands or children, or even from unrelated individuals who share HLA alleles with the husbands.
        • Prior blood transfusions can also lead to presensitization, because platelets and white blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical. (MCQ)
      • Antibody-dependent acute humoral rejection
  • Occurs in recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of the donor
      • cause injury by several mechanisms, including
  • complement-dependent cytotoxicity
  • inflammation
        • antibody-dependent cell-mediated cytotoxicity.
      • manifests as rejection vasculitis.
  • Rejection of Kidney Grafts
      • Hyperacute Rejection.
        • occurs within minutes or hours after transplantation. (MCQ)
        • A hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid,
      • Acute Rejection.
        • occur within days of transplantation in the untreated recipient
        • may appear suddenly months or even years later, after immunosuppression has been used and terminated.
        • Any of cellular or humoral immune mechanisms may predominate.
        • Histologically
  • humoral rejection is associated with vasculitis(MCQ)
  • cellular rejection is marked by an interstitial mononuclear cell infiltrate. (MCQ)
        • Acute cellular rejection
          • most commonly seen within the initial months after transplantation
          • CD8+ T cells cause(MCQ)
            • tubular damage
            • endothelitis.
  • The recognition of cellular rejection is important because, in the absence of an accompanying humoral rejection, patients respond well to immunosuppressive therapy(MCQ)
        • Acute humoral rejection (rejection vasculitis)
          • mediated by antidonor antibodies
          • it is manifested mainly by damage to the blood vessels.
          • associated with extensive necrosis of the renal parenchyma.
          • Deposition of the complement breakdown product C4d in allografts is a strong indicator of humoral rejection, because C4d is produced during activation of the complement system by the antibody-dependent classical pathway(MCQ)
      • Chronic Rejection.
      • In recent years acute rejection has been significantly controlled by immunosuppressive therapy, and chronic rejection has emerged as an important cause of graft failure. (MCQ)
      • present clinically with a progressive renal failure manifested by a rise in serum creatinine over a period of 4 to 6 months. (MCQ)
      • Chronic rejection is dominated by
  • vascular changes
  • interstitial fibrosis
        • tubular atrophy with loss of renal parenchyma
  • The vascular changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries
  • chronic transplant glomerulopathy
      • glomeruli may show scarring, with duplication of basement membranes;
    • Methods of Increasing Graft Survival
      • In kidney transplants, there is substantial benefit if all the polymorphic HLA alleles are matched (both inherited alleles of HLA-A,B and DR).
      • HLA matching is usually not even done for transplants of liver, heart, and lungs  (MCQ)
      • Immunosuppressive therapy
  • Cyclosporine
  • works by blocking activation of a transcription factor called nuclear factor of activated T cells (NFAT) (MCQ)
          • NFAT is required for transcription of cytokine genes, in particular, the gene that encodes IL-2. (MCQ)
  • azathioprine
          • inhibits leukocyte development from bone marrow precursors) (MCQ)
  • steroids
          • block inflammation
  • rapamycin and mycophenolate mofetil
          • both of which inhibit lymphocyte proliferation
  • monoclonal anti–T-cell antibodies
          • monoclonal anti-CD3 antibodies  (MCQ)
          • antibodies against the IL-2 receptor α chain [CD25], which opsonize and eliminate the cells and may also block T-cell activation). (MCQ)
  • administration of proteins that bind to B7 costimulators
          • interrupts the interaction between the B7 molecules on the dendritic cells of the graft donor with the CD28 receptors on host T cells (MCQ)
  • prevents host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization  (MCQ)
  • Bone marrow transplantation
        • the recipient is irradiated to destroy the immune system (and sometimes, cancer cells) and to create a graft bed.
      • Graft-versus-host (GVH) disease
        • occurs in any situation in which immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and the transferred cells recognize alloantigens in the host.
  • Where is GVHD seen
          • most commonly in BMT
          • transplantation of solid organs rich in lymphoid cells (e.g., the liver) (MCQ)
          • transfusion of unirradiated blood.
        • to minimize GVH disease, BMT is done between donor and recipient that are HLA-matched   (MCQ)
        • Acute GVH disease
          • occurs within days to weeks after allogeneic BMT
          • the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines. (MCQ)
            • Involvement of skin in GVH disease is manifested by a generalized rash that may lead to desquamation in severe cases. (MCQ)
            • Destruction of small bile ducts gives rise to jaundice,
            • mucosal ulceration of the gut results in bloody diarrhea.
          • Although tissue injury may be severe, the affected tissues are usually not heavily infiltrated by lymphocytes.
  • It is believed that in addition to direct cytotoxicity by CD8+ T cells, considerable damage is inflicted by cytokines released by the sensitized donor T cells.
        • Chronic GVH disease
          • These patients have extensive cutaneous injury, with destruction of skin appendages and fibrosis of the dermis.
          • The changes may resemble systemic sclerosis  (MCQ)
          • Chronic liver disease manifested by cholestatic jaundice is also frequent. Damage to the gastrointestinal tract may cause esophageal strictures.
          • The immune system is devastated, with
          • involution of the thymus
          • depletion of lymphocytes in the lymph nodes.
          • the patients experience recurrent and life-threatening infections
          • Some patients develop manifestations of autoimmunity, postulated to result from the grafted CD4+ helper T cells reacting with host B cells and stimulating these cells, some of which may be capable of producing autoantibodies. (MCQ)
        • GVH disease is mediated by T lymphocytes contained in the donor bone marrow, depletion of donor T cells before transfusion virtually eliminates the disease.
        • This protocol, however, has proved to be a mixed blessing:
          • GVH disease is ameliorated
          • But it increases incidence of (MCQ)
  • graft failures
  • EBV-related B-cell lymphoma
            • recurrence of disease in leukemic patients
        • multifaceted T cells that mediate GVH disease also
  • are required for engraftment of the transplanted marrow stem cells (MCQ)
  • suppression of EBV-infected B-cell clones
          • control of leukemic cells. (MCQ)
        • graft-versus-leukemia effect  (MCQ)
  • Deliberate induction of graft-versus-leukemia effect by infusion of allogeneic T cells is being used in the treatment of chronic myelogenous leukemia when patients relapse after bone marrow transplantation.
    • Immunodeficiency is a frequent complication of bone marrow transplantation.
      • Cytomegalovirus-induced pneumonitis can be a fatal complication. (MCQ)