The T-cell suppressive effect of bufadienolides: structural requirements for their immunoregulatory activity

Many studies indicate that substances similar to cardenolides and bufadieno lides naturally occur in mammals. The majority of previous studies focused on their cardiovascular, renal, and central nervous action. We analyzed the immunoregulatory property of 52 bufadienolides. I Human T-cells were stimu lated "in vitro" with mitogens or alloantigens in the presence of bufadieno lides. The most active compound totally inhibited T-cell activity at a conc entration of 0.75 pmol/10(5) cells. This effect is 16 384 x stronger than t hat of cortisol and 256 X stronger than that of cyclosporin A or tacrolimus . Preactivated T cells were downregulated and, most importantly, suppressed viable T cells could not be restimulated. Lack of the 17 beta -lactone rin g dramatically reduced the activity of bufadienolides. Substitution at C3 a lso affected their function: components with a 3-OH group were up to 1000 X stronger than those without. The replacement of 14P-OII with an epoxy-grou p slightly decreased the activity. Because there is evidence that the latte r change abolishes the cardiac activity, this finding is relevant for thera peutic applications in which immunosuppression without the risk of cardioto xicity is attempted. One of the substances analyzed in this study was Prosc illaridin A. A similar bufadienolide occurs naturally in mammals. We specul ate that bufadienolides represent an important bioregulatory link between t he cardiovascular, nervous and immune systetns. (C) 2001 Elsevier Science B .V. All rights reserved.