Immunosuppressive effect of FK-506 on in vitro lymphocyte alloactivation: synergism with cyclosporine A.

Abstract

Recent studies have described a new potent immunosuppressive drug FK-506 (FK) that induces considerable prolongation of allograft survival.1–3 This drug is isolated from Streptomyces tsukubaensis, has a molecular weight of 822 daltons, and is structurally different from cyclosporine A (CsA). In vitro investigations have demonstrated a strong inhibitory effect on lymphocyte activation that appears to be mediated by blocking of interleukin 2 (IL-2) release.4 Our studies have extended these findings by showing that FK inhibits secondary proliferation of alloreactive T lymphocytes generated from mixed lymphocyte reaction (MLR) cultures or propagated from organ transplant biopsy specimens with cellular infiltrates.5 The in vitro immunosuppressive effect of FK is generally several hundredfold greater than that of CsA. On the other hand, FK does not inhibit secondary proliferation of activated T cells stimulated by IL-2. With respect to the possibility that FK could be used together with CsA as an immunosuppressive drug regimen to prolong allograft survival, we studied in vitro effects of low doses of these drug combinations on lymphocyte proliferation. The results demonstrate synergism between FK and CsA in their inhibition of both primary lymphocyte alloactivation and secondary proliferation of alloreactive T cells. This in vitro synergism may have clinical application in that low doses of FK and CsA combinations may be effective in increasing transplant survival.