Immunologic Mechanisms

  • The HLA system is a key factor in most reactions. Reactions are mediated by either T lymphocytes or by antibody. The major types of hypersensitivity reactions involved are types II and IV.

  • The ABO system, best characterized as the major blood group antigens, is also important because these antigens are expresed on all cells except those in the central nervous system. Thus, matching for ABO compatibility is important for transplantation.

  • T-cell mediated reactions: Can be either CD4+ cells generating delayed hypersensitivity reactions after recognizing foreign HLA class II (DR) antigens or cytotoxic CD8+ cells recognizing foreign HLA class I (A,B, or C) antigens. The donor tissue or donor lymphocytes within the transplanted tissue carry the offending HLA antigens.

  • Antibody mediated reactions: These can be mediated through complement-mediated cytotoxicity, antibody-dependent cytotoxicity (ADCC), or immune complexes.

Organ System Pathology

  • Renal transplants: three classic modes of rejection are described. HLA matching for both class I and class II antigens improves survival:

    • Hyperacute rejection: previous sensitization through transfusion, pregnancy, or infections (through HLA cross-reacting bacterial or viral antigens) leads to preformed antibody that causes immediate (minutes to hours) vascular injury via ADCC.

    • Acute rejection: Cellular infiltrates with both CD4+ and CD8+ cells are present. Occurence is sometimes within days, but usually within months (and sometimes years later when immunosuppressive therapy is discontinued). Humoral immunity is also involved in acute rejection, and necrotizing vasculitis occurs; intimal proliferation results. Ag-Ab complexes play a role.

    • Chronic rejection: There is intimal fibrosis with vascular thickening, leading to ischemic changes. Mononuclear infiltrates with prominent plasma cells are present. Both T-cell and humoral mechanisms are involved.

  • Liver transplants: HLA is less important than simple matching of organ size (since most of these are done in children). There are two modes of rejection:

    • Acute rejection: seen within two months, there are mixed inflammatory portal and central vein infiltrates.

    • chronic rejection: at some later time, with continued inflammation, portal fibrosis, arteriolar thickening, and bile ductular necrosis occurs.

  • Heart transplants: HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in relationship to signs of rejection seen on endomyocardial biopsy. There are two modes of rejection:

    • Acute cellular rejection: there are lymphocytic infiltrates and possible myocardial fiber necrosis.

    • Acute vascular rejection: immunoglobulin deposition occurs in small arteries and produces a vasculitis.

  • Bone marrow transplants: HLA matching is important. A distinct problem is graft versus host disease (GVHD) which results from the donor lymphocytes attacking the recipient tissues having the offending HLA antigens. Chemotherapy agents used to prepare the patient for marrow transplantation may result in hepatic veno-occlusive disease in the weeks following transplantation.