Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Nathan R. Martinez, Petra Augstein, Antonis K. Moustakas, George K. Papadopoulos, Silvia Gregori, Luciano Adorini, David C. Jackson, Leonard C. Harrison

Research output: Contribution to journalArticle

Abstract

Insulin is a major target of the autoimmune response associated with destruction of pancreatic β cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice. Here we show that proinsulin B24-C36 peptide binds to I-Ag7, the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4+ T cells that, in the absence of CD8+ T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24-C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24-C36, and its core sequence B25-C34, bind to Kd, the NOD mouse MHC class I molecule, and elicit CD8+ CTLs. When the CD8+ T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to Kd, the residual CD4+ T cell epitope, B24-C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.

Original languageEnglish
Pages (from-to)1365-1371
Number of pages7
JournalJournal of Clinical Investigation
Volume111
Issue number9
DOIs
Publication statusPublished - May 2003

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Proinsulin
Inbred NOD Mouse
Type 1 Diabetes Mellitus
Epitopes
T-Lymphocyte Epitopes
C-Peptide
Peptides
Insulin
T-Lymphocytes
Intranasal Administration
Adoptive Transfer
Autoantigens
Valine
Regulatory T-Lymphocytes
Autoimmunity
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Martinez, N. R., Augstein, P., Moustakas, A. K., Papadopoulos, G. K., Gregori, S., Adorini, L., ... Harrison, L. C. (2003). Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. Journal of Clinical Investigation, 111(9), 1365-1371. https://doi.org/10.1172/JCI200317166

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. / Martinez, Nathan R.; Augstein, Petra; Moustakas, Antonis K.; Papadopoulos, George K.; Gregori, Silvia; Adorini, Luciano; Jackson, David C.; Harrison, Leonard C.

In: Journal of Clinical Investigation, Vol. 111, No. 9, 05.2003, p. 1365-1371.

Research output: Contribution to journalArticle

Martinez, NR, Augstein, P, Moustakas, AK, Papadopoulos, GK, Gregori, S, Adorini, L, Jackson, DC & Harrison, LC 2003, 'Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide', Journal of Clinical Investigation, vol. 111, no. 9, pp. 1365-1371. https://doi.org/10.1172/JCI200317166
Martinez, Nathan R. ; Augstein, Petra ; Moustakas, Antonis K. ; Papadopoulos, George K. ; Gregori, Silvia ; Adorini, Luciano ; Jackson, David C. ; Harrison, Leonard C. / Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 9. pp. 1365-1371.
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