Week 14: lessons 40,41, 42 . IMMUNOPHARMACOLOGY: Pharmacology of immuno-suppressants and stimulants

The importance of the immune system in protecting the body against harmful foreign molecules is well recognized. However, in some instances, this protection can result in serious problems. For example, the introduction of an allograft (that is, the graft of an organ or tissue from one individual to another who is not genetically identical) can elicit a dam- aging immune response, causing rejection of the transplanted tissue. Transplantation of organs and tissues (for example, kidney, heart, or bone marrow) has become routine due to improved surgical techniques and better tissue typing. Also, drugs are now available that more selectively inhibit rejection of transplanted tissues while preventing the patient from becoming immunologically compromised (Figure 40.1). Earlier drugs were nonselective, and patients frequently succumbed to infection due to suppression of both the antibody-mediated (humoral) and cell-mediated arms of the immune system. Today, the principal approach to immunosuppressive therapy is to alter lymphocyte function using drugs or antibodies against immune proteins. Because of their severe toxicities when used as monotherapy, a combination of immunosuppressive agents, usually at lower doses, is generally employed. [Note: Immunosuppressive therapy is also used in the treatment of auto immune diseases. For example, corticosteroids can control acute glomerulonephritis.] Immunosuppressive drug regimens usually consist of anywhere from two to four agents with different mechanisms of action that disrupt various levels of T-cell activation. The immune activation cascade can be described as a three-signal model. Signal 1 constitutes T-cell triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC). Signal 2, also referred to as costimulation, occurs when CD80 and CD86 on the sur- face of APCs engage CD28 on T cells. Both Signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the calcium- calcineurin pathway, which is targeted by cyclosporine and tacrolimus. These pathways trigger the production of cytokines such as interleukin (IL)-2, IL-15, CD154, and CD25. IL-2 then binds to CD25 (also known as the IL-2 receptor) on the surface of other T cells to activate mammalian tar- get of rapamycin (mTOR), providing Signal 3, the stimulus for T-cell proliferation. Immunosuppressive drugs can be categorized according to their mechanisms of action: 1) Some agents interfere with cytokine produc- tion or action; 2) others disrupt cell metabolism, preventing lymphocyte proliferation; and 3) mono- and polyclonal antibodies block T-cell surface molecule

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