Murine Antithymocyte Globulin Therapy Alters Disease Progression in NOD Mice by a Time-Dependent Induction of Immunoregulation

  1. Greg Simon1,
  2. Matthew Parker1,
  3. Vijayakumar Ramiya2,
  4. Clive Wasserfall1,
  5. Yanfei Huang3,
  6. Damien Bresson4,
  7. R. Fletcher Schwartz1,
  8. Martha Campbell-Thompson1,
  9. Lauren Tenace1,
  10. Todd Brusko1,
  11. Song Xue2,
  12. Abraham Scaria5,
  13. Michael Lukason5,
  14. Scott Eisenbeis5,
  15. John Williams5,
  16. Michael Clare-Salzler1,
  17. Desmond Schatz2,
  18. Bruce Kaplan6,
  19. Matthias Von Herrath4,
  20. Karl Womer3 and
  21. Mark A. Atkinson1
  1. 1Department of Pathology, University of Florida, Gainesville, Florida
  2. 2Department of Pediatrics, University of Florida, Gainesville, Florida
  3. 3Department of Medicine, University of Florida, Gainesville, Florida
  4. 4La Jolla Institute for Allergy and Immunology, La Jolla, California
  5. 5Genzyme Corporation, Framingham, Massachusetts
  6. 6Department of Medicine, University of Illinois-Chicago, Chicago, Illinois
  1. Address correspondence and reprint requests to Mark A. Atkinson, Department of Pathology, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610. E-mail: atkinson{at}ufl.edu

Abstract

OBJECTIVE—Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation.

RESEARCH DESIGN AND METHODS—A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes.

RESULTS—We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4+CD25+ regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo.

CONCLUSIONS—These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 26 November 2007. DOI: 10.2337/db06-1384.

    G.S. and M.P. contributed equally to this work and, with regard to authorship, should be considered interchangeably.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1384.

    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.

    • Accepted November 16, 2007.
    • Received September 29, 2006.
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  1. Diabetes vol. 57 no. 2 405-414
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