Suppression of the humoral response to anti-CD3 monoclonal antibody

Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145-2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival--and, in some instances, resulted in a lethal anaphylactic reaction. In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.