Certain Fungal Metabolites Are Immunosuppressants

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Cyclosporin A (CsA), FK506 (tacrolimus), and rapamycin (sirolimus) are fungal metabolites with immunosuppressive properties. Although chemically unrelated, CsA and FK506 have similar actions. Both drugs block activation of resting T cells by inhibiting the transcription of genes encoding IL-2 and the high-affinity IL-2 receptor (IL-2R), which are essential for activation. CsA and FK506 exert this effect by binding to cytoplasmic proteins called immunophilins, forming a complex that blocks the phosphatase activity of calcineurin. This prevents the formation and nuclear translocation of the cytoplasmic subunit NFATc and its subsequent assembly into NFAT, a DNA-binding protein necessary for transcription of the genes encoding a number of molecules important to T-cell activation (see Figure 10-11). Rapamycin is structurally similar to FK506 and also binds to an immunophilin. However, the rapamycin-immunophilin complex does not inhibit calcineurin activity; instead, it blocks the proliferation and differentiation of activated TH cells in the G1 phase of the cell cycle. All three drugs, by inhibiting TH-cell proliferation and thus TH-cell cytokine expression, reduce the subsequent activation of various effector populations involved in graft rejection, including TH cells, TC cells, NK cells, macrophages, and B cells.

The profound immunosuppressive properties of these three agents have made them a mainstay of heart, liver, kidney, and bone-marrow transplantation. Cyclosporin A has been shown to prolong graft survival in kidney, liver, heart, and heart-lung transplants. In one study of 209 kidney transplants from cadaver donors, the 1-year survival rate was 64% among recipients receiving other immunosuppressive treatments and 80% among those receiving cyclosporin A. Similar results have been obtained with liver transplants (Figure 21-8). Despite these impressive results, CsA does have some negative side effects, the most notable of which is toxicity to the kidneys. Acute nephrotoxicity is quite common, in some cases progressing to chronic nephrotoxicity and drug-induced kidney failure. FK506 and rapamycin are 10-100 times more potent as immune suppressants than CsA, and therefore can be administered at lower doses and with fewer side effects than CsA.

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Time after transplantation, months

Time after transplantation, months

FIGURE 21-8

Comparison of the survival rate of liver transplants in 84 patients who were immunosuppressed with azathioprine and corticosteroids (black) with the survival rate in 55 patients who were immunosuppressed with cyclosporin A and corticosteroids (blue). [Adapted from S. M. Sabesin and J. W. Williams, 1987, Hosp. Pract. 15(July):75]

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