MOVIE 16.1 6-TG increases the DNA’s sensitivity to mutations induced by the ultraviolet radiation in sunlight. Thus, patients treated with azathioprine have the longterm side-effect of increased risk of skin cancer. Azathioprine also generates 6-thioguanine triphosphate (6-thio-GTP), which in T cells binds to the small GTPase Rac1 in place of GTP and suppresses its activity. Signaling from CD28 co-stimulation requires Rac1, and T cells therefore do not receive the anti-apoptotic signals from co-stimulation and instead undergo apoptosis. Mycophenolate mofetil, the 2-morpholinoethyl ester of mycophenolic acid, is the newest addition to the family of cytotoxic immunosuppressive drugs; it works in a similar fashion to azathioprine. It is metabolized to mycophenolic acid, which inhibits the enzyme inosine monophosphate dehydrogenase, thus blocking the de novo synthesis of guanosine monophosphate.
Azathioprine and mycophenolate are less toxic than cyclophosphamide, which is metabolized to phosphoramide mustard, which alkylates DNA. Cyclophosphamide is a member of the nitrogen mustard family of compounds, which were originally developed as chemical weapons. It has a range of highly toxic effects including inflammation of and hemorrhage from the bladder, known as hemorrhagic cystitis, and induction of bladder neoplasia.
16-3 Cyclosporin A, tacrolimus, rapamycin, and JAK inhibitors with various T-cell signaling pathways.
Three noncytotoxic alternatives to the cytotoxic drugs are available as immunosuppressants and are widely used to treat transplant recipients. These are cyclosporin A, tacrolimus (previously known as FK506), and rapamycin (also known as sirolimus). Cyclosporin A is a cyclic decapeptide derived from a soil fungus found in Norway, Tolypocladium inflatum. Tacrolimus is a macrolide compound from the filamentous bacterium Streptomyces tsukabaensis, found in Japan; macrolides are compounds that contain a many-membered lactone ring to which is attached one or more deoxysugars. Rapamycin, another macrolide, is derived from Streptomyces hygroscopicus, found on Easter Island (‘Rapa Nui’ in Polynesian—hence the name of the drug). All three compounds exert their pharmacological effects by binding to members of a family of intracellular proteins known as the immunophilins, forming complexes that interfere with signaling pathways important for the clonal expansion of lymphocytes.
As explained in Section 7-14, cyclosporin A and tacrolimus block T-cell proliferation by inhibiting the phosphatase activity of the Ca2+-activated protein phosphatase calcineurin, which is required for the activation of the transcription factor NFAT. Both drugs reduce the expression of several cytokine genes that are normally induced on T-cell activation (Fig. 16.4), including the gene encoding interleukin (IL)-2, which is an important growth factor for T cells (see Section 9-16). Cyclosporin A and tacrolimus inhibit T-cell proliferation in response to either specific antigens or allogeneic cells, and are used extensively in medical practice to prevent the rejection of allogeneic organ grafts. Although the major immunosuppressive effects of both drugs are probably the result of inhibition of T-cell proliferation, they also act on other cells and have a large variety of other immunological effects (see Fig. 16.4).