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Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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/Fc
2a
protein, a potentially cytolytic protein that is also a high-affinity
receptor site specific antagonist for the IL-15R
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/Fc2a were
comparably effective in a semiallogeneic model system, and combined
treatment with IL-15 mutant/Fc2a 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/Fc2a 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.
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