FK-506 and cyclosporine A (CsA) immunomodulation of the human gut mucosal immune system

Abstract

FK-506 and cyclosporine A (CsA) are two immunosuppressive drugs used in the treatment of patients after liver and small intestine transplantation. A clinical advantage of FK-506 over CsA has been observed in these patients. Although the immunomodulation of both drugs has been well documented in the circulatory immune system, their effect on the mucosal immune system is not well established. In this study, the effect of FK-506 on the human gut mucosal immune system was compared to CsA. Proliferation of human colonic lamina propria lymphocytes (LPL) was measured by DNA synthesis and ornithine decarboxylase (ODC) activity. Results show that FK-506 and CsA suppress LPL DNA proliferation in a dose-dependent manner. FK-506 had a stronger antiproliferative effect compared to CsA. Moreover, the antiproliferative effect of both drugs was not dependent on monocytes or monocyte-associated factors (IL-1 beta, IL-6). In addition, exogenous addition of IL-2 did not restore the suppressive effect of either drug on LPL DNA synthesis. We conclude that: (1) both drugs have an antiproliferative effect on the human mucosal immune system; and (2) the stronger effect of FK-506 on human LPL compared to CsA may explain its superior clinical response observed in patients after liver/small intestine transplantation.