These two drugs inhibit calcineurin by first binding to an immunophilin molecule; cyclosporin A binds to the cyclophilins, and tacrolimus to the FK-binding proteins (FKBPs). Immunophilins are peptidyl-prolyl cis–trans isomerases, but their isomerase activity is not relevant to the immunosuppressive activity of the drugs that bind them. Rather, the immunophilin:drug complexes bind and inhibit the Ca2+-activated serine/threonine phosphatase calcineurin. In a normal immune response, the increase in intracellular calcium ions in response to T-cell receptor signaling activates the calcium-binding protein
Fig. 16.4 Cyclosporin A and tacrolimus inhibit lymphocyte and some granulocyte responses.
T lymphocyte Reduced expression of IL-2, IL-3, IL-4, GM-CSF, TNF-˜ Reduced proliferation following decreased IL-2 production Reduced Ca2+-dependent exocytosis of granule-associated serine esterases Inhibition of antigen-driven apoptosis calmodulin; calmodulin then activates calcineurin (see Fig. 7.18). Binding of the immunophilin:drug complex to calcineurin prevents the latter’s activation by calmodulin; the bound calcineurin is unable to dephosphorylate and activate NFAT (Fig. 16.5). Calcineurin is found in other cells besides T cells, but its levels in T cells are much lower than in other tissues. T cells are therefore particularly susceptible to the inhibitory effects of these drugs.
Cyclosporin A and tacrolimus are effective immunosuppressants but are not problem-free. As with the cytotoxic agents, they affect all immune responses indiscriminately. This can be countered by carefully varying the dose of drug given during the course of a response. During organ transplantation, for example, high doses are required during the time of grafting, but once the graft has become established the dose can be decreased in order to allow useful protective immune responses while maintaining adequate suppression of the residual response to the grafted tissue. This balance is difficult to achieve and requires careful monitoring of the patient. These drugs also have effects on many different tissues and thus can have broad side-effects, such as injury to kidney tubule epithelial cells. Finally, treatment with these drugs is relatively expensive, because they are complex natural products that must be taken for long periods. Nevertheless, at present they are the immunosuppressants of choice in clinical transplantation, and they are also being tested in a variety of autoimmune diseases, especially those that, like graft rejection, are mediated by T cells.
Rapamycin has a different mode of action from either cyclosporin A or tacrolimus. Like tacrolimus, rapamycin binds to the FKBP family of immunophilins, but the rapamycin:immunophilin complex does not inhibit calcineurin activity. Instead, it inhibits a serine/threonine kinase known as mTOR (mammalian target of rapamycin), which is involved in regulating cell growth and proliferation (see Section 7-17). The mTOR pathway can be activated by different upstream signaling pathways, including the Ras/MAPK pathway and