Immunoregulatory effects of N9-benzyl- and N7-benzyl-8-bromoguanines

In this study we investigated the effects of two guanine derivatives, 9-ben zyl- (I) and 7-benzyl-8-bromoguanines (II) on the proliferation of human T- cell leukemia and T-cell lymphoma, normal human peripheral blood mononuclea r cells (PBMC), and mouse Th1 (pGL10) and Th2 (D10.G4.1) clones. We also as sessed their effects on cytokine production (IL-3, JL-10 and IFN-gamma) in PBMC, T-cell lymphoma, HUT78 (IL-2), and murine Th1 (IL-2) and Th2 (IL-4 an d IL-5) clones. These compounds were synthesize as analog of known inhibito rs of purine nucleoside phosphorylase (PNP) 8-amino-9-benzyl-guanine. These compounds suppressed proliferation of human leukemia MOLT-4 cells, human c utaneous lymphoma HUT78 cells and normal PMBC, Compound II was a significan tly more potent inhibitor than compound I. Exogenous recombinant human IL-2 reversed the anti-proliferative effects of both compounds on HUT78 cells. These compounds had low toxicity to human EBV-transformed B-lymphocytes. Bo th compounds suppressed the production of IL-2 by activated human HUT78 cel ls, IFN-gamma by PBMC and did not affect IL-3 and IL-10 production in PBMC. Compound I inhibited anti-CD3-activated IL-2 secretion from the murine Th1 clone. The murine Th2 clone was less sensitive to both compounds as compar ed with Th1. The production of IL-4 and IL-5 by this clone was not suppress ed. Thus, it has been shown that not only 9-substituted guanines but also t heir 7-isomers selectively inhibit T-cell functions and both selectively in hibit Th1-related cytokines secretion. (C) 1999 International Society for I mmunopharmacology. Published by Elsevier Science Ltd. All rights reserved.