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Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide
Nathan R. Martinez, … , David C. Jackson, Leonard C. Harrison
Nathan R. Martinez, … , David C. Jackson, Leonard C. Harrison
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1365-1371. https://doi.org/10.1172/JCI17166.
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Article Metabolism

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

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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.

Authors

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

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Figure 1

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Intranasal proinsulin B24–C36 induces CD4+ T cells that block adoptive t...
Intranasal proinsulin B24–C36 induces CD4+ T cells that block adoptive transfer of diabetes. Female 8-week-old NOD mice (n = 4 per group) were given 40 μg of proinsulin B24–C36 peptide or OVA protein in 10 μl PBS, intranasally on three alternating days. Two weeks after the last treatment, the mice were killed and 107 pooled splenocytes from mice treated with proinsulin B24–C36 (filled circles) or OVA (open circles), or 107 pooled splenocytes from mice treated with proinsulin B24–C36 either selected for CD4+ cells (filled triangles) or depleted of either CD4+ (filled inverted triangles) or CD8+ (filled squares) cells, were cotransferred with 107 pooled splenocytes from recently NOD female mice into irradiated young NOD male recipients (n = 8 or 12 per group). The development of diabetes in recipients after transfer was monitored by measuring blood glucose every 2 weeks. Results are representative of five similar experiments.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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