Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide
- Author(s)
- Martinez, NR; Augstein, P; Moustakas, AK; Papadopoulos, GK; Gregori, S; Adorini, L; Jackson, DC; Harrison, LC;
- Details
- Publication Year 2003-05,Volume 111,Issue #9,Page 1365-1371
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Publication Type
- Journal Article
- Abstract
- Insulin is a major target of the autoimmune response associated with destruction of pancreatic P 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-A(g7), the MHC class 11 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 K-d, 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.
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Keywords
- MHC CLASS-I; MYELIN BASIC-PROTEIN; BETA-CELL FUNCTION; ORAL INSULIN; T-CELLS; NOD MICE; AUTOANTIGEN; TOLERANCE; MOLECULE; DISEASE
- Publisher's Version
- https://doi.org/10.1172/JCI200317166
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2003-05-01 12:00:00