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As a potential novel approach to preventing renal allograft rejection, we investigated whether the proliferative response of lymphocytes to mismatched HLA class II antigens in mixed lymphocytic culture (MLC) can be suppressed by antagonists of cyclic nucleotide phosphodiesterase (PDE) isozymes. Cilostamide, an antagonist of isozyme PDE3 and, to an even greater extent, in combination with rolipram, an antagonist of isozyme PDE4, markedly suppressed (delta = -60%; p < 0.01) the mitogenic proliferative response of lymphocytes in MLC to HLA-DR alloantigens from unrelated donors. These observations suggest that the selective PDE isozyme antagonists might have potential as novel drugs in "signal transduction-targeted" pharmacotherapy of renal transplant rejection.