An antagonist mutant IL-15/Fc promotes transplant tolerance

Background. IL-15 is a proinflammatory and antiapoptotic T-cell growth factor that plays an important role in a variety of autoimmune disorders and transplant rejection. To inhibit IL-15 function and to target IL-15 receptor (IL-15R) bearing cells, we have generated a unique lytic antagonistic mutant IL-15/Fc fusion protein (mIL-15/Fc). Methods. In this study, we further examined the efficacy of mIL-15/Fc in preventing allograft rejection cross minor and major histocompatibility barriers. Results. A short-course treatment with mIL-15/Fc fusion protein is sufficient to prevent cardiac allograft rejection and induce antigen-specific tolerance in minor histocompatibility complex-mismatched recipients, and permit prolonged cardiac allograft survival in fully MHC mismatched recipients. In addition, mIL-15/Fc treatment, in combination with a suboptimal dose of anti-CD154 antibody, confers permanent cardiac allograft engraftment in a fully MHC-mismatched mouse strain combination. In a murine islet allograft model, mIL-15/Fc monotherapy is capable to permit permanent allograft survival in 50% fully MHC-mismatched recipients. Conclusion. Immunochemistry studies demonstrated that prolonged graft survival was accompanied by reduced intragraft mononuclear cell infiltration and pro-inflammatory cytokine gene expression in the mIL-15/Fc treated recipients. Moreover, parallel experiments employing a mutated nonlytic IgG2a Fc demonstrate that the Fc portion of mIL-15/Fc contributes to the overall efficacy of the molecule in vivo.