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

  1. Andrew B. Adams1,
  2. Nozomu Shirasugi1,
  3. Megan M. Durham1,
  4. Elizabeth Strobert2,
  5. Dan Anderson2,
  6. Phyllis Rees1,
  7. Shannon Cowan1,
  8. Huaying Xu1,
  9. Yelena Blinder1,
  10. Michael Cheung1,
  11. Dianne Hollenbaugh3,
  12. Norma S. Kenyon4,
  13. Thomas C. Pearson12 and
  14. Christian P. Larsen12
  1. 1Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia
  2. 2Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia
  3. 3Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey
  4. 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.

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    1. Diabetes vol. 51 no. 2 265-270
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