Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation

Figure 1 Three-signal pathway of lymphocyte activation and targets of inhibitory agents. The elucidation of lymphocyte activation pathways has facilitated the development of novel immunosuppressive drugs. At the molecular level, T-cell-mediated rejection is explained by the three-signal model of lymphocyte activation. Signal 1 occurs when alloantigen-bearing APCs engage alloantigen-reactive naïve and memory T-cells and trigger their activation; alloantigen recognition is transduced through the TCR-CD3 complex. Signal 2 occurs when CD80 and CD86 on the surface of APCs engage CD28 on T-lymphocytes, providing T-lymphocyte co-stimulation. Together, signals 1 and 2 activate several signal transduction pathways, including the calcium-calcineurin pathway, the MAPK pathway, and the NF-κB pathway, which in turn, trigger the expression of many cytokines. Several of these cytokines (IL-2, IL-4, IL-7, IL-15, and IL-21) induce proliferation (signal 3) through PI3K and mTOR pathways. Ag: Antigen; APC: Antigen-presenting cell; MAPK: Mitogen-activated protein kinase; MHC: Major histocompatibility complex; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa B; PI3K: Phosphatidylinositol 3-kinase; TCR: T-cell receptor.