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 costi mulation blockade might represent a CD8(+) and IL-I 5/IL-15R(+)-dependent p rocess. For this analysis, we have used an IL-15 mutant/Fc gamma 2a protein , a potentially cytolytic protein that is also a high-affinity receptor sit e specific antagonist for the IL-15R alpha receptor protein, as a therapeut ic agent. The IL-15-related fusion protein was used as monotherapy or in co mbination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fc gamma 2a were comparably effective in a se miallogeneic model system, and combined treatment with IL-15 mutant/Fc gamm a 2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC -mismatched strain combination known to be refractory to costimulation bloc kade treatment, combined treatment with both fusion proteins proved to be h ighly 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 C TLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fc gamma 2a protein blocked a CD8(+) T cell-dominated rejection processes. This protect ion was linked to a blunted proliferative response of alloreactive T cells as well silencing of CTL-related gene expression events. Hence, we have dem onstrated that targeting the IL-15/IL-15R pathway represents a new and pote nt strategy to prevent costimulation blockade-resistant CD8(+) T cell-drive n rejection.