M9 Transplantation Immunology

• Transplantation Immunology


  Branch of science to deal with the tissues and organ which is essential to our body to maintain homeostasis
• Vital organs involved in transplantation

  • Kidney
  • Bone marrow stem cells
  • Liver
  • Pancreas
• Transplantation


  • Minor issue in medical field
  • Rejection and improper typing is the main culprit of the issue
• Major Histocompatibility Complex (MHC)


  Cluster of genes found on the short arm of chromosome 6 at band 21
• HLA (Human Leukocyte Antigens)


  Cell surface proteins that play a central role in immune recognition and initiation of immune responses
• Transplanted tissue may trigger a destructive mechanism, rejection, if the recipient's cells recognize the MHC protein products on the surface of the transplanted tissue as foreign
• Classical (transplant) HLA antigens

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


  Inherited as one maternal and one paternal HLA haplotype
• There is a 25 percent chance that any two siblings will inherit the same two haplotypes (i.e., are HLA identical), a 50 percent chance of being HLA haploidentical (i.e., share one of two HLA haplotypes), and a 25 percent chance of being HLA nonidentical (i.e., share neither HLA haplotype)
• The Three HLA Classes

  • HLA Class I
  • HLA Class II
  • HLA Class III
• HLA Class I


  • Consists of an alpha chain, a highly polymorphic glycoprotein, encoded within the MHC on chromosome 6
  • 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
• HLA Class I Loci

  • HLA-A
  • HLA-B
  • HLA-C
• HLA Class II Loci

  • HLA-DN
  • HLA-DO
  • HLA-DP
  • HLA-DQ
  • HLA-DR
• HLA Class I Distribution

  Most nucleated cells
• HLA Class II Distribution

  B lymphocytes, macrophages, other antigen-presenting cells, activated T lymphocytes
• HLA Class I Function

  To present endogenous antigen to cytotoxic T lymphocytes
• HLA Class II Function

  To present endogenous antigen to helper T lymphocytes
• HLA Class III Function


  Complement System gene products such as C2, C4A, C4B, and Bf complement components are incomplete but these structures are defined by genes lying between or very near the HLA-B and HLA-DR loci
• The presence of HLA was first recognized when multiple 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
• Role of Major Histocompatibility Complex and Human Leukocyte Antigens

  • Transplants are rejected if performed against MHC barriers; thus, immunosuppressive therapy is required
  • The 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
• 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
• Allorecognition


  Transplantation of cells or tissues between two individuals is classified by the genetic relatedness of the donor and the recipient
• 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


  Involves 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
  • KIRs are one of several types of cell surface molecules that regulate the activity of natural killer (NK) lymphocytes
• Immunologic tolerance


  • The acquisition of nonreactivity toward particular antigens
  • Self-recognition (tolerance) is a critical process, and the failure to recognize self-antigens can result in autoimmune disease
• Pathways to T cell tolerance

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

  • Clonal abortion
  • Clonal exhaustion
  • Functional deletion
  • Anergy
• Pathways of B cell tolerance

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


  A low concentration of multivalent antigen may cause the immature clone to abort. Tolerance of immature B cells by this mechanism is high.