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Multiple Combination Therapies Involving Blockade of ICOS/B7RP‐1 Costimulation Facilitate Long‐Term Islet Allograft Survival

In recent years a series of novel costimulatory molecules have been identified, including inducible costimulator (ICOS). In a fully major histocompatibility complex (MHC)‐mismatched mouse model of islet transplantation, we demonstrate that while monotherapy with CTLA4‐Ig, CD40 ligand monoclonal antibody (CD40L mAb) or rapamycin each improves islet allograft survival, graft rejection eventually develops. Immunohistologic analysis of rejected grafts revealed increased ICOS expression, suggesting a role for this costimulatory molecule as an alternate pathway for T‐cell activation. The combination of a blocking anti‐ICOS mAb with each of the above therapies resulted in significantly improved islet allograft survival, confirming the importance of ICOS signaling in islet allograft rejection. Mechanistic studies conducted in mice treated with anti‐ICOS mAb and rapamycin demonstrated a lack of donor‐specific immunological tolerance and an absence of regulatory T‐cell activity. However, a dramatic effect was seen on acute anti‐donor responses whereby anti‐ICOS mAb and rapamycin significantly reduced the initial expansion and function of alloreactive T cells. These data demonstrate that blockade of the ICOS/B7RP‐1 pathway has potential therapeutic benefit given its role in enhancing islet allograft survival and regulating acute alloresponses in vivo.