CTLA-4Ig in Combination with Anti-CD40L Prolongs Xenograft Survival and Inhibits Anti-Gal Ab Production in GT-Ko Mice

Abstract

The generation of GT‐Ko mice has provided unique opportunities to study allograft and xenograft rejection in the context of anti‐α1,3‐Gal antibody (anti‐Gal Ab) responses. In this study we used the allotransplantation model of C3H hearts into galactosyltransferase‐deficient (GT‐Ko) mice and the xenotransplantation model of baby Lewis rat hearts into GT‐Ko mice to investigate the ability of CTLA‐4Ig in combination with anti‐CD40L mAb to control graft rejection and anti‐Gal Ab production. Murine CTLA‐4Ig or anti‐CD40L monotherapy prolonged allograft survival, and the combination of these reagents was most immunosuppressive. However short‐term treatment with murine cytotoxic T lymphocyte associated antigen‐4 (muCTLA‐4Ig) and/or CD40 ligand (CD154) monoclonal antibodies (anti‐CD40L mAbs) was unable to induce indefinite allograft survival. CTLA‐4‐immunoglobulin fusion protein (CTLA‐4Ig) or anti‐CD40L monotherapy only marginally prolonged xenograft survival; the combination of human CTLA‐4Ig and anti‐CD40L significantly prolonged xenograft survival (74 days), while the combination of murine CTLA‐4Ig and anti‐CD40L resulted in graft survival of > 120 days. CTLA‐4Ig or anti‐CD40L monotherapy or the combination of these agents inhibited the production of alloAbs, including anti‐Gal Abs. CTLA‐4Ig or anti‐CD40L monotherapy partially controlled xenoAb and anti‐Gal Ab production, while the combination was more effective. These observations corroborate our previous observations that humoral, including anti‐Gal Ab, responses and rejection following allograft or concordant xenograft transplantation in GT‐Ko mice are T‐cell dependent and can be controlled by costimulation blockade.