[PDF][PDF] Manipulating immune responses with immunosuppressive agents that target NFAT

A Kiani, A Rao, J Aramburu - Immunity, 2000 - cell.com
Immunity, 2000cell.com
Germany and cell-surface receptors that are essential for a pro-‡ Department of Pathology
ductive immune response (Rao et al., 1997). Some of Harvard Medical School and the
immunosuppressive effects of CsA may depend on The Center for Blood Research its ability
to induce TGFß, an immunosuppressive cyto-Boston, Massachusetts 02115 kine, in diverse
cells and tissues (Suthanthiran et al., 1996). CsA or FK506 are frequently used in
combination with less specific immunosuppressants such as predni-The immune system is a …
Germany and cell-surface receptors that are essential for a pro-‡ Department of Pathology ductive immune response (Rao et al., 1997). Some of Harvard Medical School and the immunosuppressive effects of CsA may depend on The Center for Blood Research its ability to induce TGFß, an immunosuppressive cyto-Boston, Massachusetts 02115 kine, in diverse cells and tissues (Suthanthiran et al., 1996). CsA or FK506 are frequently used in combination with less specific immunosuppressants such as predni-The immune system is a complex network of cellular sone, azathioprine, methotrexate, and mycophenolate and humoral factors that ensures the integrity of the mofetil to achieve synergistic immunosuppressive eforganism by attacking potential pathogens. Sometimes fects (Suthanthiran et al., 1996; Gummert et al., 1999). this normally protective system overreacts and directs The main drawback of these immunosuppressive regiits forces at the organism itself. The clinical syndrome mens, however, is that they produce major toxic side of septic shock results from overactive host responses effects and therefore are rarely employed except in serito gram-negative bacterial infections and can be fatal ous clinical situations. because of an overwhelming production of proinflam- Our thesis in this review is that since NFAT is a valimatory cytokines. Transplantation of solid organs is dated target for two clinically important immunosupconfounded by the immunologic problem of graft rejec- pressive drugs, interference with NFAT regulation might tion, while graft-versus-host-disease is one of the major be expected to yield additional avenues for immunosupcomplications of transplantation with allogeneic bone pression. Moreover, since NFAT is only one of many marrow or peripheral blood stem cells, severely limiting calcineurin substrates, compounds that interfere selecthe application of these potentially life-saving therapeu- tively with NFAT regulation might be expected to have tic options. Other examples of inappropriate immune fewer side effects than CsA and FK506. Unfortunately, responses include allergic asthma and chronic autoim- this simple premise is complicated by the existence of mune diseases such as rheumatoid arthritis. A major multiple NFAT proteins, our incomplete knowledge of challenge for clinicians is how to suppress deleterious their regulation and function in immune and nonimmune immune responses in these diverse clinical settings. cells, and our lack of information about the mechanisms The fungal metabolites cyclosporin A (CsA) and tacrol- underlying the toxic effects of CsA and FK506. imus (FK506) are among the most potent immunosup- Here we review our current understanding of these pressive drugs available today. CsA revolutionized the points. We consider what features of NFAT regulation field of organ transplantation following its discovery in might be exploited to develop selective inhibitors of 1976 (Borel et al., 1976); it was approved for clinical use NFAT, whether such drugs would be as immunosupin 1983. Tacrolimus was described soon after (Kino et pressive as CsA or FK506, whether they would lack the al., 1987) and introduced into clinical trials in 1989. De- toxic effects of CsA and FK506, and whether they might spite their lack of structural similarity, the modes of have unexpected side effects in immune and nonimmune action of these two drugs are very similar: at the low organs. An informed understanding of these issues might concentrations relevant to their immunosuppressive ef- spur the development of better, less toxic immunosupfects, they inhibit the calcium-dependent serine/threo- pressive agents that target …
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