Inhibitors of T Cell Signaling Pathways

The calcineurin inhibitors cyclosporine and FK506 (tacrolimus) inhibit transcription of certain genes in T cells,

Anti-TCR (OKT3, Thymoglobulin)

FIGURE 16-10 Mechanisms of action of immunosuppressive drugs. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs.

Azathioprine Mycophenolate mofetil

Cyclosporine introduced

FIGURE 16-11 Influence of cyclosporine on graft survival. Five-year survival rates for patients receiving cardiac allografts increased significantly beginning when cyclosporine was introduced in 1983. (Data from Transplant Patient DataSource, United Network for Organ Sharing, Richmond, Virginia. Available at: http://207.239.150.13/tpd/. Accessed February 16, 2000.)

FIGURE 16-11 Influence of cyclosporine on graft survival. Five-year survival rates for patients receiving cardiac allografts increased significantly beginning when cyclosporine was introduced in 1983. (Data from Transplant Patient DataSource, United Network for Organ Sharing, Richmond, Virginia. Available at: http://207.239.150.13/tpd/. Accessed February 16, 2000.)

most notably those encoding cytokines such as IL-2. Cyclosporine is a fungal peptide that binds with high affinity to a ubiquitous cellular protein called cyclophilin. The complex of cyclosporine and cyclophilin binds to and inhibits the enzymatic activity of the calcium/calmodulin-activated serine/threonine phosphatase calcineurin (see Chapter 7). Because calcineurin is required to activate the transcription factor NFAT (nuclear factor of activated T cells), cyclosporine inhibits NFAT activation and the transcription of IL-2 and other cytokine genes. The net result is that cyclosporine blocks the IL-2-dependent proliferation and differentiation of T cells. FK506 is a macrolide lactone made by a bacterium that functions like cyclospo-rine. FK506 and its binding protein (called FKBP) share with the cyclosporine-cyclophilin complex the ability to bind calcineurin and inhibit its activity.

The introduction of cyclosporine into clinical practice ushered in the modern era of transplantation. Before the use of cyclosporine, the majority of transplanted hearts and livers were rejected. Now as a result of the use of cyclosporine, FK506, and other more recently introduced drugs, the majority of these allografts survive for more than 5 years (Fig. 16-11). Nevertheless, these drugs have limitations. For example, at doses needed for optimal immunosuppression cyclosporine causes kidney damage, and some rejection episodes are refractory to cyclospo-rine treatment. FK506 was initially used for liver transplant recipients, but it is now used widely for immu-nosuppression of kidney allograft recipients, including those who are not adequately controlled by cyclosporine. FK506 is also used topically for some inflammatory skin diseases.

The immunosuppressive drug rapamycin (sirolimus) inhibits growth factor-mediated T cell proliferation.

Like FK506, rapamycin binds to FKBP, but the rapamycin-FKBP complex does not inhibit calcineurin. Instead, this complex binds to and inhibits a cellular enzyme called mammalian target of rapamycin complex 1 (mTORCl), which is a serine/threonine protein kinase required for translation of proteins that promote cell survival and proliferation. mTORC1 is negatively regulated by a protein complex called tuberous sclerosis complex 1 (TSC1)-TSC2 complex. Phosphotidyinositol 3-kinase (PI3K)-Akt signaling results in phosphorylation of TSC2 and release of mTOR regulation. Several growth factor receptor signaling pathways, including the IL-2 receptor pathway in T cells, activate mTOR through PI3K-Akt, leading to translation of proteins needed for cell cycle progression. Thus, by inhibiting mTORC1 function, rapamycin blocks IL-2-driven T cell proliferation. Combinations of cyclosporine (which blocks IL-2 synthesis) and rapamycin (which blocks IL-2-driven proliferation) are potent inhibitors of T cell responses. Interestingly, rapa-mycin inhibits the generation of effector T cells but does not impair the survival and functions of regulatory T cells as much, which may promote immune suppression of allograft rejection. mTORC1 is involved in dendritic cell functions, and therefore rapamycin may suppress T cell responses by interfering with dendritic cell function as well. mTORC1 is also involved in B cell proliferation and antibody responses, and therefore rapamycin may also be effective in preventing or treating antibody-mediated rejection. In addition to rapamycin, other mTOR inhibitors have been developed for immunosuppression of allograft recipients and for cancer therapy.

Other molecules involved in cytokine and T cell receptor signaling are also targets of immunosuppressive drugs that are in early trials for treatment or prevention of allograft rejection. These target molecules include JAK3, a kinase linked to signaling of various cytokine receptors, including IL-2, and protein kinase C, an essential kinase in T cell receptor signaling.

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