Calcineurin Inhibitor–Free CD28 Blockade-Based Protocol Protects Allogeneic Islets in Nonhuman Primates

Calcineurin Inhibitor–Free CD28 Blockade-Based Protocol Protects Allogeneic Islets in Nonhuman Primates Andrew B. Adams 1 , Nozomu Shirasugi 1 , Megan M. Durham 1 , Elizabeth Strobert 2 , Dan Anderson 2 , Phyllis Rees 1 , Shannon Cowan 1 , Huaying Xu 1 , Yelena Blinder 1 , Michael Cheung 1 , Dianne Hollenbaugh 3 , Norma S. Kenyon 4 , Thomas C. Pearson 1 2 and Christian P. Larsen 1 2 1 Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 2 Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 3 Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 4 Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida Abstract Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti–IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti–IL-2R regimen ( n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone ( n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-γ enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model. Footnotes Address correspondence and reprint requests to Drs. Christian P. Larsen or Thomas C. Pearson, Emory Transplant Center, Suite 5105, WMRB1639 Pierce Dr., Atlanta, GA 30322. E-mail: clarsen{at}emoryhealthcare.org or tpearson{at}emoryhealt