Induction of transplantation tolerance in adults using donor antigen and anti-CD4 monoclonal antibody

The T-cell-mediated immune response usually results in the rapid destruction of organ allografts transplanted between murine strains incompatible for major and minor histocompatibility antigens. This response may be modified by pretreatment with either donor-specific antigen or anti-CD4 monoclonal antibody. Previous work by others has shown that combined treatment of mice with soluble protein antigens and anti-CD4 monoclonal antibody can produce antigen-specific B cell unresponsiveness that continues long after the nonspecific immunosuppressive effect of the mAb treatment has resolved. Following this principle we have shown that adult C3H/He mice can be made specifically unresponsive to vascularized C57BL/10 cardiac allografts by pretreating the recipient with donor alloantigen under the cover of a brief course of mAb against CD4. A full-dose response analysis shows that the dose of mAb is critically important for the successful induction of tolerance. Tolerance induction using this protocol is dependent on treatment with donor major histocompatibility complex antigens and occurs in the presence of marked depletion but not complete elimination of the CD4+ T cell subset. The unresponsiveness to alloantigen is antigen specific, as determined by the ineffectiveness of third-party (C57BL/10) alloantigen when combined with anti-CD4 mAb to induce long-term survival of BALB/c allografts in C3H/He recipients. The tolerant state is specific and effective in the long-term as indicated by the specific acceptance of C57BL/10 skin grafts in recipients with surviving C57BL/10 cardiac allografts. This study provides a simple method for the successful induction of specific transplantation tolerance in the adult across a full H-2 major and minor antigen mismatch strain combination. The results illustrate the important role of the CD4 molecule in the T cell response to alloantigen in vivo and suggest possibilities for the therapeutic manipulation of complex immune reactions.