Transplant rejection mechanisms

Mechanism of Action An immunologic agent that suppresses the immunologically mediated inflammatory response by inhibiting inosine monophosphate dehydrogenase, an enzyme that deprives lymphocytes of nucleotides necessary for DNA and RNA synthesis, thus inhibiting the proliferation of T and B lymphocytes. Therapeutic Effect Prevents transplant rejection. 

Mechanism of Action An immunologic agent that inhibits T-lymphocyte activation by binding to intracellular proteins, forming a complex, and inhibiting phosphatase activity. Therapeutic Effect Suppresses the immunologically mediated inflammatory response prevents organ transplant rejection. 

Type IV Reactions Also termed delay-type hypersensitivity reaction, these take 48-72 h to develop and are not antibody-mediated. Antigens are recognized by CD4+ and/or CD8+ cells in the context of MHC class restrictions on APCs. These reactions are T-cell-mediated where activated T cells release cytokines, resulting in the development of granulomas from macrophages. These mechanisms are responsible for symptoms that may include transplant rejection, contact dermatitis, leprosy, tuberculosis and sarcoidosis. 

Rocha PN, Plumb TJ, Crowley SD, Coffman TM. 2003. Effector mechanisms in transplant rejection. Immunol Rev. 196 51-64. 

Understanding the molecular basis of immune responses has allowed the definition of mechanisms by which cellular function is altered by local hormones or autacoids in infections, cancer, autoimmune diseases, and organ transplant rejection. These processes present targets for therapeutic intervention. 

Hypericum perforatum (St. John s wort), which is used for mild depression, is an inducer of cytochrome P-450. It caused a rapid dramatic fall in ciclosporin blood concentrations, resulting in acute heart transplant rejection in two patients aged 61 and 63 years (262). It produces an average 50% reduction in ciclosporin blood concentrations (263). At least three other case reports have clearly confirmed that St. John s wort is dangerous in transplant patients, because it produced a rapid and dramatic reduction in blood ciclosporin concentration and resulted in acute organ rejection in two patients (264—266). Induction of CYP3A4 and/or P-glycoprotein was the most likely mechanism. 

A second form of cyclosporine-induced nephrotoxicity is acute thrombotic microangiopathy. The mechanism for induction of this toxicity is unclear but may be due to a direct toxic effect of cyclosporine on renal arterioles and glomerular capillaries. Histologically, arterioles exhibit protein deposits while glomeruli show thrombosis and endothelial cell damage. These effects are similar in nature to transplant rejection thrombotic microangiopathy, but arcuate and interlobular arteries rather than arterioles are primarily affected with transplant rejection. 

In order to fully understand the complex biochemical mechanisms by which the thymus and its hormones control the expression of immunity, it is first necessary to review briefly the organization of the thymus-dependent (T cell) immune system (Fig. I). The predominant cells of the peripheral lymphoid tissue (i.e., spleen, lymph nodes) includes both B and T lymphocytes. In the presence of foreign antigens, B lymphocytes differentiate into plasma cells, which in turn synthesize antibody thus, B cells make up the humoral arm of the immune system. In contrast, T lymphocytes are responsible for mediating all the classical cellular immune responses such as delayed type hypersensitivity skin responses, organ transplant rejections, and sensitized antitumor immunity as well as immunity toward various viral, fungal, and protozoal pathogens (Reinherz and Schlossman, 1980). 

Immunoisolation may also have an advantage in preventing the autoimmune destruction of the transplanted islets (27) by separating them from the host (T-cells or autoantibodies) by the permselective membrane. Although the detailed mechanism of islet cell damage is unknown, evidence from spontaneously diabetic BB rats indicates that the rapid failure of islet transplants, even in twins (28), may be due to a recurrence of autoimmune disease rather than the conventional transplant rejection phenomenon (29). 

Type IV. Cellular mediated. Antigens, which are localized by direct contact with body tissue and bind to these tissues, react with im-mune-sensitized T-lymphocytes, releasing cell-free factors resulting in tissue damage. Some examples of this mechanism are al-leigic contact dermatitis and graft-versus-host transplantation rejection. 

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

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