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Immunological approach to inhibit formation of anti‐antibodies to allo‐ and xenogeneic anti‐T cell immunoglobulin

Inhibitory anti‐antibodies induced in patients by xenogeneic or even by humanized anti‐T cell antibodies remain an unresolved problem. Mice also produce anti‐antibodies following injection of xeno‐ or allogeneic anti‐T cell antibodies. Here we report a principle based on sequentially applied anti‐T cell antibodies generated in different species, which results in suppressed anti‐antibody formation and prolonged immunosuppression. Thus, a single priming injection in mice of mouse (MmT1 or MmT5 differing by idiotype only) or of rat (RmT1) anti‐mouse Thy‐1 monoclonal antibodies (mAb) or of rat anti‐mouse L3T4 + Ly‐2 (RmCD4 + CD8) mAb suppressed anti‐antibody formation against subsequent booster injections of one of the above antibodies, provided that they differed in species origin from the priming antibody. Correspondingly, a sixfold and longer prolongation of 50% survival of fully mismatched skin grafts was observed. Less or no anti‐antibody suppression and little prolongation of graft surival was obtained if the ‘first’ and the ‘second’ (and following) antibody injections were of the same species, differing by iso‐ or idiotype only. Finally, the suppressive principle did not manifest itself at all if the initial antibody injection included both the first and second antibody. These findings are discussed with reference to earlier studies on hapten/carrier effects as well as on immunosuppression attributed to ‘non‐depleting’ rat anti‐CD4/CD8 T cell antibodies.