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Original Articles

Retardation or Acceleration of Diabetes in NOD/Lt Mice Mediated by Intrathymic Administration of Candidate β-Cell Antigens

  1. Marina Cetkovic-Cvrlje,
  2. Ivan C Gerling,
  3. Andrew Muir,
  4. Mark A Atkinson,
  5. John F Elliott and
  6. Edward H Leiter
  1. Jackson Laboratory Bar Harbor, Maine
  2. Department of Pathology, University of Florida Gainesville, Florida
  3. University of Alberta Edmonton, Canada
  1. Address correspondence and reprint requests to Dr. Edward H. Leiter, The Jackson Laboratory, Bar Harbor, ME 04609. E-mail: ehl{at}aretha.jax.org.
Diabetes 1997 Dec; 46(12): 1975-1982. https://doi.org/10.2337/diab.46.12.1975
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Abstract

A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt female mice strongly retards diabetogenesis. The present study used the intrathymic route of antigen administration to compare the relative efficacy of peptides/proteins derived from two major candidate pancreatic β-cell autoantigens, insulin and GAD65, to modulate diabetogenesis. Intrathymic administration of insulin B chain or recombinant human GAD65 significantly suppressed diabetogenesis during a 20-week follow-up period, whereas no protection was mediated by either insulin A chain or a synthetic peptide (A2) derived from it. Quite unexpectedly, two GAD65-derived peptides near the COOH-terminus (p34 and p35) accelerated diabetes onset. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed on cDNAs from isolated islets or whole pancreases of NOD/Lt females 4 weeks after intrathymic injections. Protection mediated by intrathymic administration with either intact islet cells or GAD65 were correlated with an upregulation of mRNA for T-helper 2 (Th2)-associated cytokines (interleukin [IL]-4, IL-10), concomitant with downregulation of Th1-associated interferon (IFN) transcripts (all normalized to T-cell receptor Cβ transcripts) in islet-infiltrating lymphocytes. Protection mediated by the intrathymic administration of insulin B chain, however, correlated only with a modest upregulation of IL-4 and IL-10 transcript levels, and no diminution in IFN-γ transcripts. In contrast, the diabetes-accelerating GAD65 p34 and p35 peptides were not associated with an immune deviation, expressing levels of IFN-γ characteristic of islet-infiltrating lymphocytes in vehicleinjected NOD controls. Hence, Th1-to-Th2 immune deviation provides only a partial explanation for peptide immunotherapy of diabetes in NOD mice. The finding that certain peptides can accelerate rather than retard diabetogenesis as a function of route and age of administration adds a cautionary note to this type of therapy.

  • Received March 17, 1997.
  • Revision received August 12, 1997.
  • Accepted August 12, 1997.
  • Copyright © 1997 by the American Diabetes Association

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December 1997, 46(12)
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Retardation or Acceleration of Diabetes in NOD/Lt Mice Mediated by Intrathymic Administration of Candidate β-Cell Antigens
Marina Cetkovic-Cvrlje, Ivan C Gerling, Andrew Muir, Mark A Atkinson, John F Elliott, Edward H Leiter
Diabetes Dec 1997, 46 (12) 1975-1982; DOI: 10.2337/diab.46.12.1975

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Retardation or Acceleration of Diabetes in NOD/Lt Mice Mediated by Intrathymic Administration of Candidate β-Cell Antigens
Marina Cetkovic-Cvrlje, Ivan C Gerling, Andrew Muir, Mark A Atkinson, John F Elliott, Edward H Leiter
Diabetes Dec 1997, 46 (12) 1975-1982; DOI: 10.2337/diab.46.12.1975
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