DOSE-DEPENDENT ENHANCING AND INHIBITORY EFFECTS OF A77-1726 (LEFLUNOMIDE) ON CYTOTOXIC T-LYMPHOCYTE INDUCTION

Leflunomide is an immunosuppressive prodrug which prevents allograft r ejection in several animal model systems and may, therefore, have clin ical application in organ transplant recipients. Although cytotoxic T lymphocytes (CTL) are an important component of the allograft rejectio n response, the effect of leflunomide on CTL development has not been thoroughly explored. In this study we have determined the effect of A7 7 1726, the active metabolite of leflunomide, on CTL induction in C57B L/6 mouse T cell cultures stimulated with anti-CD3 monoclonal antibody . Conjugate formation with P815 target cells, granzyme B enzymatic act ivity in CTL lysates, and P815 cytolysis in a Cr-51-release assay were used as determinants of in vitro CTL function. At high concentrations (10-20 mu M), A77 1726 strongly inhibited CTL generation. In contrast , a low concentration (0.5 mu M) of A77 1726 promoted CTL development. These dose-dependent opposing effects of A77 1726 on CTL induction co uld not be attributed to alterations in CD8(+) lymphocyte percentages, interleukin-2 or CD25 expression, or the ability to conjugate with P8 15 target cells. However, both interferon-gamma and granzyme B express ion were significantly decreased when CTL were induced in the presence of 10-20 mu M A77 1726, and were slightly, but not always significant ly, elevated in the presence of 0.5 mu M A77 1726. We conclude that at high concentrations A77 1726 is; a potent inhibitor of CTL induction, but a low concentration of A77 1726 enhances CTL development. (C) 199 8 International Society for Immunopharmacology. Published by Elsevier Science Ltd.