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Chapter 23: Immunotherapeutic Agents

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Cyclosporine was one of the first immunosuppressants to be used for organ transplant therapy. The mechanism of action of cyclosporine is to

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a. intercalate DNA in proliferating T cells.

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b. block purine metabolism in proliferating T cells.

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c. block CD52 on the surface of activated T cells.

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d. block the protein phosphatase activity of calcineurin.

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e. block the protein kinase activity of mTOR.

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Answer is d. Cyclosporin targets intracellular signaling pathways induced as a consequence of T-cell receptor activation. The drug binds to an immunophilin known as cyclophilin which subsequently interacts with calcineurin to inhibit its protein phosphatase activity (see Figure 23-1). Calcineurin-catalyzed dephosphorylation of the protein nuclear factor of activated T lymphocytes (NFAT) is required for movement of NFAT into the nucleus. NFAT, in turn, is required to induce a number of cytokine genes, including that for interleukin-2 (IL-2), a prototypic T-cell growth and differentiation factor.

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Figure 23-1. Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T lymphocytes. Both cyclosporine and tacrolimus bind to immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), forming a complex that binds the phosphatase calcineurin and inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement of the nuclear factor of activated T cells (NFAT) into the nucleus. NFAT is required for transcription of interleukin-2 (IL-2) and other growth- and differentiation-associated cytokines (lymphokines). Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2 receptor. Sirolimus also binds FKBP, but the FKBP-sirolimus complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase involved in cell-cycle progression (proliferation). TCR, T-cell receptor. (Reproduced with permission from Pattison JM et al. Mechanisms of allograft rejection. In Neilson EG, Couser WG, eds. Immunologic Renal Diseases. Philadelphia, PA: Lippincott-Raven; 1997. http://lww.com.)

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Tacrolimus is one of the most effective immunosuppressant drugs in routine use. The mechanism of action of tacrolimus is to

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a. intercalate DNA in proliferating T cells.

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b. block guanine nucleotide synthesis in proliferating T cells.

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c. block CD52 on the surface of activated T cells.

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d. block the protein phosphatase activity of calcineurin.

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e. block the protein kinase activity of mTOR.

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Answer is d. Although structurally unrelated to cyclosporine, tacrolimus inhibits T-cell signal transduction by almost the same mechanism. Tacrolimus binds the immunophilin FK506-binding protein-12 (FKBP-12), which is structurally related to cyclophilin, the target of cyclosporine. A complex of tacrolimus-FKBP-12, Ca2+, ...

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