Immunosuppressive mechanism of action of corticosteroids

The central issue in organ transplantation remains suppression of allograft rejection. Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways. Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids. Small-molecule immunosuppressive agents include calcineurin-inhibitors (cyclosporine, tacrolimus), Target-of-Rapamycin Inhibitors (Sirolimus, Everolimus), inhibitors of nucleotide synthesis and azathioprine. The review covers the mode of action of these drugs with a special focus on belatacept, a new promising fusion protein. Different immuo-suppressive strategies mean also different safety profiles. Common side effects include the consequences of diminished immuno- response, . infections and cancer (mainly involving the skin). Toxic side effects of immunosuppressive drugs range in a wide spectrum that involves almost every organ. The major interest of this toxic effects is the cardiovascular tolerance (with large differences from drug to drug), that are discussed seperately. The calcineurin- and mTOR-inhibitors are both metabolized by the CYP450 3A4 enzyme, which is also involved in the metabolism of many other drugs. The review discusses the most important interactions that in- or decreases the through level of these drugs.

Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.

Immunosuppressive mechanism of action of corticosteroids

immunosuppressive mechanism of action of corticosteroids


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