An antagonist IL-15/FC protein prevents costimulation blockade-resistant rejection

IL-15 is a powerful T cell growth factor (TCGF) with particular importance for the maintenance of CD8⁺ T cells. Because costimulation blockade does not result in universal tolerance, we hypothesized that "escape" from costimulation blockade might represent a CD8⁺ and IL-15/IL-15R⁺-dependent process. For this analysis, we have used an IL-15 mutant/Fcγ2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15Rα receptor protein, as a therapeutic agent. The IL-15-related fusion protein was used as monotherapy or in combination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fcγ2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fcγ2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC-mismatched strain combination known to be refractory to costimulation blockade treatment, combined treatment with both fusion proteins proved to be highly effective; >70% of recipients were tolerized. The analysis revealed that the IL-15 mutant/Fc treatment confers partial protection from both CD4⁺ and CD8⁺ T cell graft infiltration. In rejections occurring despite CTLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fcγ2a protein blocked a CD8⁺ T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cells as well silencing of CTL-related gene expression events. Hence, we have demonstrated that targeting the IL-15/IL-15R pathway represents a new and potent strategy to prevent costimulation blockade-resistant CD8⁺ T cell-driven rejection.