Transplant Immunology

Overview of Transplantation

  • Purpose of Transplants:

    • Restore function when an organ or tissue is irreparably damaged by disease or injury.

    • Address congenital absence or defects of organs or tissues.

    • Graft: Healthy tissue or organ transplanted.

    • Donor: Individual providing the tissue or organ.

    • Recipient: Individual receiving the tissue or organ.

Classification of Transplants

  • Immunological-Genetic & Antigenic Relationship:

    • Autograft: Transplant from self.

    • Syngeneic (Isograft): Between genetically identical individuals, e.g., identical twins.

    • Allograft (Homograft): Between individuals of the same species with different genetic makeup.

    • Xenograft (Heterograft): Between different species.

  • By Organ/Tissue:

    • Kidney, heart, skin transplants, etc.

Immunology and Transplantation

  • Success Factors:

    • Genetic match between donor and recipient.

    • Critical genes include those for ABO blood group antigens and MHC receptors.

Major Histocompatibility Complex (MHC)

  • HLA Gene Matching:

    • Close matching of HLA genes increases transplant success.

    • HLA genes have high genetic variability, making matching difficult.

    • HLA complex includes over 200 genes on chromosome 6, divided into Class I, II, and III.

  • Genetic Diversity:

    • HLA complex is highly diverse; over 5000 HLA alleles.

    • Each individual has 12 HLA class I and II genes (6 from each parent).

HLA Testing

  • Testing Types:

    • HLA gene typing of donor and recipient.

    • HLA antibody screening of the recipient.

    • Lymphocyte cross-matching to detect recipient antibodies against donor lymphocytes.

Recognition of Alloantigens by T Cells

  • Mechanisms:

    • Direct Recognition: Recipient's T cells recognize allogeneic MHC molecules directly.

    • Indirect Recognition: Recipient's antigen-presenting cells process and present donor MHC molecules.

Activation and Effector Functions of Alloreactive T Lymphocytes

  • T Cell Response:

    • Initiated in lymph nodes draining the graft.

    • CD4+ T Cells: Produce cytokines leading to graft inflammation.

    • CD8+ T Cells: Differentiate into cytotoxic T lymphocytes (CTLs) that kill graft cells.

Alloreactive B Cells and Alloantibodies

  • Role of Antibodies:

    • Donor-specific antibodies contribute to rejection.

    • Antibodies produced via T cell-dependent activation of B cells.

    • Target both class I and II MHC proteins and non-HLA alloantigens.

    • Cause damage through complement activation and Fc receptor-mediated cell activation.

Types of Allograft Rejection

  • Hyperacute Rejection:

    • Occurs within minutes to 24 hours.

    • Mediated by preexisting antibodies against ABO blood group antigens or MHC molecules.

    • Results in vascular thrombosis and type II hypersensitivity reaction.

  • Acute Rejection:

    • Occurs 1 week to several months post-transplant.

    • Mediated by T cells (cell-mediated) and B cells (antibody-mediated).

    • Cell-mediated: CTLs attack graft cells.

    • Antibody-mediated: Antibodies cause vasculitis and lymphocytic infiltrates.

    • Type IV hypersensitivity reaction.

  • Chronic Rejection:

    • Occurs months or years post-transplant.

    • Involves both cellular and humoral immune responses.

    • Characterized by arterial occlusion and ischemic damage.

    • Mediated by cytokines causing smooth muscle proliferation and tissue fibrosis.

    • Type II and type IV hypersensitivity reaction

Methods to Reduce Allograft Immunogenicity

  • Donor-Recipient Matching:

    • ABO blood group antigen compatibility.

    • MHC allele matching, especially for kidney transplants.

    • Preformed antibody testing.

  • Immunosuppressive Drugs:

    • Used to inhibit or kill T lymphocytes and prevent graft rejection.

Hematopoietic Stem Cell (HSC) Transplantation

  • Purpose:

    • Treat diseases caused by defects in hematopoietic lineages.

    • HSCs obtained from donor blood post-treatment with colony-stimulating factors.

  • Graft Versus Host Reaction (GVHR):

    • Occurs when donor immune cells attack recipient tissues.

    • Requires graft with immunocompetent T cells and an immunocompromised host.

    • Acute GVHR occurs 7-30 days post-transplant.

  • Immunodeficiency Post-HSC Transplantation:

    • Recipients may struggle to regenerate a complete new lymphocyte repertoire.

    • Increased susceptibility to viral, bacterial, and fungal infections.