免疫药理学课件.pptVIP

Inhibits mammalian target of rapamycin (mTOR) mTOR is a protein kinase that plays pivotal role in IL-2 receptor responses IL-2 binds to its receptor on T cells and leads to mTOR activation mTOR initiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiation Inhibition of mTOR blocks IL-2 dependent cell-cycle progression at G1→S phase transition Consequences of TOR Action Lymphocyte cell proliferation differentiation T cells B cells Antibody production Mesenchymal cell proliferation Vascular smooth muscle cells Endothelial cells Fibroblasts Properties of TOR Inhibitorssuch as Sirolimus (Rapamune) Selective blockade of cytokine signal transduction Inhibition of T cell division and proliferation Potent and effective immunosuppression Potential for synergy with other immunosuppressants Sirolimus (Rapamune) other theoretical actions include blockade of B cell Ig synthesis inhibition of antibody-dependent cellular toxicity inhibition of lymphocyte activated killer cells inhibition of natural killer cells inhibition of immune and nonimmune cell proliferation (via inhibition of growth factor signaling) (may explain antitumor actions) Sirolimus (Rapamune) Bioavailability low oral absorption hepatic metabolism by CYP4503A4 (drug interactions may occur) long half-life (60 hours) Adverse Effects thrombocytopenia, hyperlipidemia, rash lacks direct end organ toxicity but increased incidence impaired renal function when combined with cyclosporine Adrenocortical Hormones Inhibition of IL-1 and TNF gene expression and synthesis Decreased activation of T lymphocytes by decreasing IL-1 release Decreased neutrophil functions esp chemotaxis Decreased antibody production (high doses) Decreased release of kinins and proinflammatory eicosanoids (prostaglandins and leukotrienes) Corticosteroid Immunosuppression Decreased cell-mediated immune reactions that mediate rejection of organ transplants Mechanisms: decreased activati