Pathophysiology Of Transplant Rejection

The immune system has evolved to protect us against invasion from foreign pathogens and not renal grafts, and many of the same immune mechanisms that protect us against pathogens are also responsible for graft rejection. Enough divergence does exist between the immune response to transplants and pathogens that complete immunosuppression is not required for graft survival. Transplant research has shown that suppression of cellular, not humoral, immunity is critical for graft survival.

A newly transplanted graft is immediately identified as foreign by circulating T-lymphocytes that recognize class II human leukocyte antigen (HLA) on the surface of the donor organ. Once bound to these antigens, the T-lymphocytes differentiate, proliferate, and produce a wide array of soluble proteins called lymphokines. Lymphokines feed back to increase T-lymphocyte activation and stimulate B-cell antibody production against the graft. Specialized helper T-lymphocytes called cytotoxic T-lymphocytes are stimulated to directly attack the graft by attaching to cell-surface HLA class I antigens.

Identification of the specific components of the immune system responsible for graft rejection allows for a targeted approach to immunosuppression. Pharmacologic protocols have been developed to selectively inhibit those components of the immune system responsible for graft rejection. 7 The doses of these immunosuppressants are then carefully adjusted to balance the risks of graft rejection with the risks of infection.

Azathioprine is a purine analogue. Metabolites of azathioprine are incorporated into DNA and RNA strands, inhibiting their synthesis and function. The immunosuppressant action of azathioprine occurs through blocking gene activation of stimulated I-lymphocytes. Azathioprine is prescribed at a dose of 2 mg/kg/day on a continuous basis as maintenance antirejection therapy. Noncompliance with azathioprine has been associated with a high rejection rate. Deleterious effects of azathioprine include leukopenia, thrombocytopenia, hepatotoxicity, and increased risk of neoplasm.

Corticosteroids have a role both in antirejection maintenance and during acute rejection episodes. Corticosteroids inhibit antigen-stimulated I-lymphocyte proliferation and inhibit lymphokine production. A major drawback of the use of steroids is their nonselectivity of immunosuppression, effecting both the cellular and humoral immunity and resulting in significantly increased risk of infection. Other deleterious effects of steroids include osteoporosis, hyperglycemia, hyperkalemia, and growth suppression in children.

Cyclosporine (CYA) and Tacrolimus (FK506) are both macrolide antibiotics produced by fungi. Although structurally unrelated, both CYA and FK506 agents block the proliferation of helper and cytotoxic T cells and inhibit lymphokine release. Unlike azathioprine and steroids, CYA and FK506 do not interfere with activation and proliferation of suppressor T lymphocytes. In fact, their major immunosuppressant effect may be directly related to their activation of suppressor cells. Both CYA and FK506 have similar toxic profiles, including, nephrotoxicity, hemolytic uremic syndrome, and hypertension. CYA has a vital role in maintenance antirejection therapy: CYA trough whole blood levels between 150 and 300 ng/mL are associated with graft survival.

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