IL-2-RESISTANT HYPORESPONSIVENESS INDUCED BY CD4 MABS IN OKT3-ACTIVATED HUMAN T-CELLS IS REVERSED BY CD45RA TRIGGERING

CD4 monoclonal antibodies (mAbs) are potent immunosuppressive agents w hich have been shown to induce in vivo tolerance to antigens and alloa ntigens and are presently evaluated in humans in the treatment of auto immune diseases, In previous studies, we observed that clinical improv ement of CD4 mAb-treated psoriasis patients was achieved without deple tion of CD4(+) lymphocytes and at nonsaturating CD4 mAb concentrations , suggesting a functional blockade of CD4(+) lymphocyte responses. In this study, we demonstrate that priming of normal human CD4(+) T cells by immobilized OKT3 (iOKT3) in the presence of CD4 mAbs in soluble ph ase induces a hyporesponsiveness following subsequent restimulation by iOKTS in the absence of CD4 mAbs. This hyporesponsiveness was not ass ociated with increased cell death during priming or restimulation cult ures and could be reversed by the combination of phorbol ester + ionom ycin, demonstrating a functional blockade of viable cells by CD4 mAbs, Following iOKT3 restimulation, hyporesponsive cells showed a lack of blast transformation and CD25 expression and were not able to respond to IL-2 since addition of high doses of exogenous IL-2 +/- CD28 mAbs d id not reverse the hyporesponsiveness. However, costimulation with CD4 5RA mAb completely reversed the hyporesponsiveness, suggesting that CD 45 controlled the CD4-mediated hyporesponsiveness. (C) 1996 Academic P ress, Inc.