Pig Embryonic Pancreatic Tissue as a Source for Transplantation in Diabetes

Transient Treatment With Anti-LFA1, Anti-CD48, and FTY720 Enables Long-Term Graft Maintenance in Mice With Only Mild Ongoing Immunosuppression

  1. Dalit Tchorsh-Yutsis1,
  2. Gil Hecht1,
  3. Anna Aronovich1,
  4. Elias Shezen1,
  5. Yael Klionsky1,
  6. Chava Rosen1,
  7. Rivka Bitcover1,
  8. Smadar Eventov-Friedman1,
  9. Helena Katchman1,
  10. Sivan Cohen1,
  11. Orna Tal1,
  12. Oren Milstein1,
  13. Hideo Yagita2,
  14. Bruce R. Blazar3 and
  15. Yair Reisner1
  1. 1Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
  2. 2Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;
  3. 3Cancer Center and Department of Pediatrics, Division of Pediatric Hematology/Oncology and Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.
  1. Corresponding author: Yair Reisner, yair.reisner{at}weizmann.ac.il.
  1. D.T.-Y. and G.H. contributed equally to this work.

Abstract

OBJECTIVE Defining an optimal costimulatory blockade–based immune suppression protocol enabling engraftment and functional development of E42 pig embryonic pancreatic tissue in mice.

RESEARCH DESIGN AND METHODS Considering that anti-CD40L was found to be thrombotic in humans, we sought to test alternative costimulatory blockade agents already in clinical use, including CTLA4-Ig, anti-LFA1, and anti-CD48. These agents were tested in conjunction with T-cell debulking by anti-CD4 and anti-CD8 antibodies or with conventional immunosuppressive drugs. Engraftment and functional development of E42 pig pancreatic tissue was monitored by immunohistology and by measuring pig insulin blood levels.

RESULTS Fetal pig pancreatic tissue harvested at E42, or even as early as at E28, was fiercely rejected in C57BL/6 mice and in Lewis rats. A novel immune suppression comprising anti-LFA1, anti-CD48, and FTY720 afforded optimal growth and functional development. Cessation of treatment with anti-LFA1 and anti-CD48 at 3 months posttransplant did not lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced diabetes.

CONCLUSIONS This novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received January 26, 2009.
    • Accepted April 15, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 58 no. 7 1585-1594
  1. All Versions of this Article:
    1. db09-0112v1
    2. 58/7/1585 most recent