A MOUSE MODEL FOR THE PRECLINICAL EVALUATION OF IMMUNOSUPPRESSIVE EFFECTOR FUNCTIONS OF HUMAN ISOTYPES - THE HUMAN IGG1 ISOTYPE IS SUPERIORTO IGG3

Antibodies against T cells are widely used as immunosuppressive agents in clinical therapy. As effector functions of chimeric or humanized a nti-T cell antibodies cannot be predicted in vitro, we compared T cell -depleting effects of human isotypes in vivo with their immunosuppress ive consequences in a mouse BMT model. This system is based on chimeri c antibodies with a mouse pan T cell specificity and human constant re gions. To secure optimal immunosuppression, the specificity for Thy-1. 2-one of the best-characterized T cell antigens-was selected, as Thy-1 .2-specific antibodies prevent graft-versus-host disease in fully mism atched mice. Chimeric mouse anti-Thy-1.2 antibody with the human IgG1 Fc part was found to be equally effective in preventing graft-versus-h ost disease mortality as the highly protective anti-Thy-1.2 mouse IgG2 a isotype, while human IgG3 was far less effective. This was not predi ctable by measuring the degree of T cell depletion in peripheral blood . T cell depletion in lymph nodes, however, exactly reflected the resu lts obtained in the BRIT system. In addition, this system offers the a dvantage of assessing the influence of reduced antigen density by usin g heterozygous Thy-1.2 mice.