Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens

Marina Cetkovic-Cvrlje, Ivan Gerling, Andrew Muir, Mark A. Atkinson, John F. Elliott, Edward H. Leiter

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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 daring 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 vehicle-injected 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.

Original languageEnglish (US)
Pages (from-to)1975-1982
Number of pages8
JournalDiabetes
Volume46
Issue number12
StatePublished - Dec 1 1997

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Inbred NOD Mouse
Antigens
Peptides
Insulin
Interferons
Islets of Langerhans
Interleukin-4
Interleukin-10
Up-Regulation
Lymphocytes
Injections
Autoantigens
T-Cell Antigen Receptor
varespladib methyl
Immunotherapy
Thymus Gland
Reverse Transcription
Pancreas
Down-Regulation
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Cetkovic-Cvrlje, M., Gerling, I., Muir, A., Atkinson, M. A., Elliott, J. F., & Leiter, E. H. (1997). Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens. Diabetes, 46(12), 1975-1982.

Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens. / Cetkovic-Cvrlje, Marina; Gerling, Ivan; Muir, Andrew; Atkinson, Mark A.; Elliott, John F.; Leiter, Edward H.

In: Diabetes, Vol. 46, No. 12, 01.12.1997, p. 1975-1982.

Research output: Contribution to journalArticle

Cetkovic-Cvrlje, M, Gerling, I, Muir, A, Atkinson, MA, Elliott, JF & Leiter, EH 1997, 'Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens', Diabetes, vol. 46, no. 12, pp. 1975-1982.
Cetkovic-Cvrlje M, Gerling I, Muir A, Atkinson MA, Elliott JF, Leiter EH. Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens. Diabetes. 1997 Dec 1;46(12):1975-1982.
Cetkovic-Cvrlje, Marina ; Gerling, Ivan ; Muir, Andrew ; Atkinson, Mark A. ; Elliott, John F. ; Leiter, Edward H. / Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate β-cell antigens. In: Diabetes. 1997 ; Vol. 46, No. 12. pp. 1975-1982.
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