Calcineurin Inhibitor–Free CD28 Blockade-Based Protocol Protects Allogeneic Islets in Nonhuman Primates
- Andrew B. Adams1,
- Nozomu Shirasugi1,
- Megan M. Durham1,
- Elizabeth Strobert2,
- Dan Anderson2,
- Phyllis Rees1,
- Shannon Cowan1,
- Huaying Xu1,
- Yelena Blinder1,
- Michael Cheung1,
- Dianne Hollenbaugh3,
- Norma S. Kenyon4,
- Thomas C. Pearson12 and
- Christian P. Larsen12
- 1Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia
- 2Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia
- 3Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey
- 4Diabetes 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}emoryhealthcare.org.
Received for publication 20 October 2001 and accepted in revised form 27 November 2001. Posted on the World Wide Web at http://www.diabetes.org/diabetes_rapids on 4 January 2002.
A.B.A. and N.S. contributed equally to this study.
ELISpot, enzyme-linked immunospot; IEQ, islet equivalents; IFN-γ, interferon-γ; mAb, monoclonal antibody; MHC, major hisocompatibility complex; MST, median survival time; POD, postoperative day.
