Murine Anti-Thymocyte 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. Atkinson (atkinson{at}ufl.edu)1
  1. From the 1Department of Pathology,
  2. 2Department of Pediatrics,
  3. 3Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida, 32610, USA
  4. 4La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, La Jolla, California, 92121, USA
  5. 5Genzyme Corporation, One Mountain Drive, Framingham, Massachusetts, 01701, USA
  6. 6University of Illinois-Chicago, 820 South Wood Street, Chicago, Illinois, 60612, USA

    Abstract

    Objective: Anti-lymphocyte serum can reverse overt type 1 diabetes (T1D) 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 anti-lymphocyte 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 the development of T1D.

    Results: We observed that mATG attenuates T1D 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 the frequency of antigen presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age dependent fashion, the frequency as well as the functional activity of CD4+CD25+ regulatory T cells. Adoptive transfer/co-transfer studies of T1D also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo.

    Conclusions: These findings indicate an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of anti-thymocyte globulin and suggest time-dependent windows for the ability to delay or reverse T1D exist based on the capacity to enhance the functional activity of regulatory T cells.

    Footnotes

      • Received September 29, 2007.
      • Accepted November 16, 2007.

    This Article

    1. Diabetes
    1. Online-Only Appendix
    2. All Versions of this Article:
      1. db06-1384v1
      2. 57/2/405 most recent