**6.6 Mammalian target of rapamycin (mTOR) inhibitors**

Sirolimus is a macrocyclic antibiotic produced by *Streptomyces hygroscopicus* fermentation. It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects. Sirolimus binds to FKBP-12 and modulates the activity of mTOR, which inhibits IL-2-mediated signal transduction and results in T- and B-cell cycle arrest in the G1-S phase. Sirolimus is associated with numerous adverse effects including leukopenia, thrombocytopenia, anemia, hypercholesterolemia, hypertriglyceridemia, proteinuria, ae well as leg oedema. Contrary to Cyclosporine and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase of T lymphocyte activation, signal transduction and lymphocyte clonal proliferation. So sirolimus is not used early after transplant because of wound dehiscence. Also sirolimus carries a black box warning that cautions against possible development of early postttransplant hepatic artery thrombosis. Although sirolimus binds to FKBP-12 like tacrolimus, the complex inhibits mTOR, not calcineurin. Therefore, sirolimus acts synergistically with Cyclosporine, and when used in combination with other immunosuppressants, it has few side effects. Also, it indirectly inhibits several T lymphocyte-specific kinases and phosphatases, preventing their transition from G1 to the S phase of the cell cycle. In a similar manner, sirolimus prevents plasma cell differentiation, reducing the production of IgM, IgG, and IgA antibodies. It has also been associated with mucositis, delayed wound healing, lymphocele formation, pneumonitis, and prolonged delayed graft function. It is also active against tumors that are PI3K/AKT/mTOR-dependent.

#### **6.7 Everolimus**

**Everolimus** is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Everolimus may have a role in transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.
