Transplantation Immunology

• Transplantation


  Potentially lifesaving treatment for end-stage organ failure, cancers, autoimmune diseases, immune deficiencies, and a variety of other diseases
• HLA system


  Largest immunologic barrier to successful allogeneic organ transplantation
• Major histocompatibility complex (MHC)


  Cluster of genes found on the short arm of chromosome 6 at band 21
• Classical (transplant) HLA antigens

  • HLA-A
  • HLA-B
  • HLA-C (Class I)
  • HLA-DR
  • HLA-DQ
  • HLA-DP (Class II)
• HLA proteins


  Encoded by a set of closely linked genes on the short arm of chromosome 6 in the major histocompatibility complex (MHC)
• HLA haplotypes


  Inherited from parental chromosomes, with offspring receiving one maternal and one paternal HLA haplotype
• There is a 25% chance that any two siblings will inherit the same two HLA haplotypes (HLA identical), a 50% chance of being HLA haploidentical (share one of two HLA haplotypes), and a 25% chance of being HLA nonidentical (share neither HLA haplotype)
• HLA Classes


  • Class I (HLA-A, B, C)
  • Class II (HLA-DR, DQ, DP)
  • Class III
• HLA Class I


  • Consists of an alpha chain, a highly polymorphic glycoprotein, encoded within the MHC on chromosome 6, which noncovalently associates with beta-2 microglobulin, a nonpolymorphic glycoprotein, encoded by a non-HLA gene on chromosome 15
• HLA Class II


  • Composed of alpha chains and beta chains encoded within the MHC
• HLA Class III


  • Bear no clear relationship to class I and II molecules aside from their genetic linkage (presence of the gene in or near the MHC complex), involved in immunologic phenomenon because they represent components of the complement pathways
• Role of MHC and HLA

  Presence of HLA was first recognized when multiple transfused patients experienced transfusion reactions despite proper crossmatching, caused by leukocyte antibodies rather than by antibodies directed against erythrocyte antigens, MHC gene products have an important role in clinical immunology, transplants are rejected if performed against MHC barriers, immunosuppressive therapy is required, class I and class II molecules can also bind to self-antigens produced in the normal process of cellular protein degradation, usually not recognized by the T cell receptor (tolerance), in transplant patients, most immune responses are generated against the foreign MHC molecules
• Transfused patients experienced transfusion reactions despite proper crossmatching. It was discovered that these reactions were caused by leukocyte antibodies rather than by antibodies directed against erythrocyte antigens. These same antibodies were subsequently discovered in the sera of multiparous women.
• MHC gene products


  Have an important role in clinical immunology
• Transplants are rejected if performed against MHC barriers; thus, immunosuppressive therapy is required
• MHC antigens are of primary importance and are second only to the ABO antigens in influencing the genetic basis of survival or rejection of transplanted organs
• Class I and class II molecules can also bind to self-antigens produced in the normal process of cellular protein degradation. Usually, these are not recognized by the T cell receptor (TCR; tolerance)
• In transplant patients, most immune responses are generated not from bacterial antigens, viral antigens, or self-antigens, but from the presentation of alloepitopes derived from the transplanted tissue to circulating T lymphocytes
• HLA-A and HLA-B


  The most important HLA antigens
• Everyone has two types of each of these major HLA antigens; there are many different subtypes of HLA-A and of the others
• The best possible match is 6/6; the worst possible match is 0/6
• In kidney allografts, HLA compatibility exerts the strongest influence on long-term kidney survival
• HLA Associated Diseases


  • Ankylosing spondylitis (B27)
  • Reiter's syndrome (B27)
  • Psoriasis vulgaris (Cw6)
  • Rheumatoid arthritis (DR4)
  • Behcet's disease (B5)
  • Type 1 diabetes (DR3)
  • Gold-induced nephropathy (DR5)
  • Congenital adrenal hyperplasia (B47)
  • Chronic lymphatic leukemia (DR5)
  • Kaposi's sarcoma (Mediterranean) (DR5)
• Although the degree of association between HLA antigens and other diseases may be statistically significant, it is not strong enough to be of diagnostic or prognostic value
• Transplantation terms


  • Autograft
  • Syngeneic graft
  • Allograft
  • Xenograft
• Direct allorecognition


  Recipient T cells bind and respond directly to foreign (allo) HLA proteins on graft cells
• Indirect allorecognition


  The immune system recognizes foreign HLA proteins by the uptake, processing, and presentation of foreign HLA proteins by recipient antigen-presenting cells to recipient T cells
• Indirect allorecognition plays a predominant role in acute and chronic rejection
• ABO blood group antigens


  The only blood group system that impacts clinical transplantation
• Anti-A or anti-B antibodies develop in individuals lacking the corresponding blood group antigens. ABO blood group incompatibility is a barrier to solid organ transplantation, because these antibodies can bind the corresponding antigens that are expressed on the vascular endothelium
• Killer immunoglobulin-like receptor (KIR) system

  Polymorphic genetic system that impacts allogeneic transplantation
• Immunologic tolerance


  The acquisition of nonreactivity toward particular antigens
• Pathways of T cell tolerance

  • Clonal abortion
  • Functional deletion
  • T cell suppression
• Pathways of B cell tolerance

  • Clonal abortion
  • Clonal exhaustion
  • Functional deletion
  • Antibody-forming cell blockade
• Hyperacute rejection


  Mediated by preformed antibody that reacts with donor vascular endothelium
• Acute rejection


  Characterized by parenchymal and vascular injury, with interstitial cellular infiltrates containing predominantly CD8-positive T cells as well as CD4 T cells and macrophages
• Chronic rejection


  Results from a process of graft arteriosclerosis characterized by progressive fibrosis and scarring with narrowing of the vessel lumen due to proliferation of smooth muscle cells
• CD8 cells


  • Likely mediate cytotoxic reactions to foreign MHC-expressing cells
• CD4 cells


  • Likely produce cytokines and induce delayed-type hypersensitivity (DTH) reactions
• Antibody may also be involved in acute graft rejection by binding to vessel walls, activating complement, and inducing transmural necrosis and inflammation as opposed to the thrombosis typical of hyperacute rejection