CD8+ T Cells Resistant to Costimulatory Blockade Are Controlled by an Antagonist Interleukin-15/Fc Protein

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Abstract

Background.

Although permanent engraftment is often achieved with new therapeutics, chronic rejection and graft failure still occur. As the importance of CD8+ T cells in rejection processes has been underlined in various transplant models, and as interleukin (IL)-15 is involved in the activation of CD8+ T cells, we hypothesize that CD8+ T cell “escape” from costimulation blockade might be a IL-15/IL-15R dependent process.

Methods.

In a murine islet allograft model employing a fully major histocompatibility complex–mismatched strain combination of Balb/c donors to CD4−/− C57BL/6 recipients, a monotherapy with the IL-15 antagonist, IL-15 mutant/Fcγ2a, or the costimulatory blockade molecule, CTLA4/Fc, was used. In addition to monitoring graft survival, infiltration of alloreactive immune cells was analyzed by histology and immunohistochemistry, and alloimmune response of proliferative CD8+ T cells was measured in vivo.

Results.

Sixty percent of the recipients treated with CTLA4/Fc acutely rejected their islet allograft, comparable to untreated control animals (50% survival). In contrast, the IL-15 antagonist proved to be highly effective, with 100% of recipients accepting their allograft. Immunohistology study demonstrated a remarkable decrease of CD8+ T-cell intragraft infiltration in IL-15 mutant/Fcγ2a treated animals with well-preserved islet architecture and a reduced frequency of proliferating alloreactive CD8+ T cells in comparison with that of untreated and CTLA4/Fc treated groups.

Conclusions.

In this study, we determined the efficacy and potential therapeutic benefit of the IL-15 antagonist on CD4-independent CD8+ T-cell responses to alloantigens. Targeting the IL-15/IL-15R pathway represents a potent strategy to prevent rejection driven by CD8+ T cells resistant to costimulation blockade.

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