Induction and suppression of anti‐antibodies to syngeneic T cell‐binding antibodies in mice

Considerable effort is being invested in antibody gene technologies for production of species‐adapted anti‐T cell antibodies which can overcome formation of neutralizing anti‐antibodies (anti‐Ab). By establishing a mouse model for the generation of syngeneic anti‐T cell MoAb, we addressed the question of whether ideally species‐adapted T cell‐binding antibodies can prime mice to produce anti‐Ab. Two anti‐Thy‐1.2 MoAbs of IgG2a (MmTC) or IgM (MmTC‐IgM) isotype were generated in congenic C57Bl/6‐Thy‐1.1 mice. Three injections of MmTC in C57Bl/6‐Thy‐1.2 or (C57Bl/6‐Thy‐1.2×C57Bl/6‐Thy‐1.1)F 1 hybrids where they act as syngeneic anti‐T cell MoAbs induced low anti‐Ab. When MmTC was injected as Igh‐mismatched antibody in CBA/J mice, high titre anti‐MmTC antibodies were measured and fully mismatched skin allografts rejected within 26 days. MmTC injected twice weekly in syngeneic C57Bl/6 mice induced low anti‐MmTC and prolonged graft survival up to day 117. In contrast, retreatment induced anti‐MmTC with graft rejection within 32 days. Thus, upon retreatment, the immunosuppressive effects of MmTC were inhibited to a similar extent as that seen after antibody treatment in Igh‐mismatched mice. However, a recently analysed immunological principle to suppress anti‐Ab against T cell binding allo‐ or xenoantibodies by preinjection of T cell‐depleting antibody with species differences in heavy chains also suppressed syngeneic anti‐Ab after MmTC retreatment. This effect was accompanied by prolonged graft survival. Thus, our data indicate that inhibitory anti‐Ab must be considered in humans even when treated with fully species‐adapted anti‐T cell MoAb, but may be suppressed by preinjection of a Fc region‐mismatched anti‐T cell antibody.