Cyclosporin A, FK-506, and Rapamycin: Pharmacologic Probes of Lymphocyte Signal Transduction

Abstract

CsA, FK-506, and rapamycin are microbial products with potent immunosuppressive properties that result primarily from a selective inhibition of T lymphocyte activation. Although chemically unrelated, CsA and FK-506 affect a similar subset of calcium-associated signaling events involved in the regulation of lymphokine gene expression, activation-driven T-cell death and exocytosis. Rapamycin has structural similarity with FK-506 but suppresses T-cell activation at a different level, mainly through inhibition of proliferation induced by growth-promoting lymphokines. CsA interacts with an abundant 17 kDa protein, termed cyclophilin, that possesses peptidyl-prolyl cis-trans isomerase (PPIase) activity. Additional, minor cyclophilin-like molecules have been identified. Both FK-506 and rapamycin interact with FKBP, a 12 kDa protein, which, although unrelated to cyclophilin, is also abundant and ubiquitous, has a similar enzymatic activity, and is a member of a larger family of FKBPs. All three immunosuppressants inhibit the PPIase activity of their respective binding proteins. However, nonimmunosuppressive analogs of CsA and FK-506 are also inhibitory, indicating that inhibition of PPIase activity is not directly implicated in immunosuppression. Moreover, only a small fraction of the cellular pool of the major forms of cyclophilin or FKBP needs to be occupied by the drugs in order to achieve maximal immunosuppression. These observations suggest that complexes formed between the drugs and their major binding proteins may affect the function of other, unidentified, molecules or, alternatively, that minor binding proteins may play a role in the drugs' action. Further characterization of the biochemical processes altered by CsA, FK-506, and rapamycin should yield important insights into the signal transduction pathways involved in T-cell activation and should help in the development of novel immunosuppressive agents.

Activation-induced cell death in B lymphocytes

“…Furthermore, in several immature B-lymphoma cells such as in murine B-lymphoma cells WEHI-231 [19] or BKS-2 [18], in Burkitt s lymphoma cells [20], and in the human B-lymphoma cell line, B104 [21], elevation of cytosolic free calcium seems to be sufficient to induce growth inhibition and apoptosis. In agreement with this notion, immunosuppressant cyclosporin A (CsA) that inhibits calcineurin (reviewed in [22]), protects some of these B-lymphoma cells from calcium-induced, as well as from anti-IgM-induced growth arrest and apoptosis [23]. However, the role of immunosuppressants in immature B-lymphoma cells is still controversial since several other groups reported that CsA, FK506 and rapamycin actually induce growth arrest and apoptosis in WEHI-231 cells [24], [25].…”

Glycine Inhibits Growth of T Lymphocytes by an IL-2-Independent Mechanism

“…8, left; Ref. 28). Therefore, it was hypothesized that glycine would blunt increases in [Ca 2ϩ ] i and thereby reduce IL-2 production.…”

Effects of dietary conjugated linoleic acids on cellular immune response of piglets after cyclosporin A injection

“…So we hypothesized that CLA could ameliorate the cellular immunosuppression in piglets. Cyclosporin A (CsA), a cellular immunosuppressive drug, prevents the synthesis of T-cell cytokines by blocking a late stage signaling pathway initiated by the T-cell receptor, which affects the production of interleukin-2 (IL-2); hence, T-cell proliferation is affected (Lillehoj, 1987;Hill et al, 1989;Sigal and Dumont, 1992). The objective of this study was to evaluate the effects of 2% dietary CLA on the cellular immune response of piglets intramuscularly injected with CsA.…”