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

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    Author
    Martinez, NR; Augstein, P; Moustakas, AK; Papadopoulos, GK; Gregori, S; Adorini, L; Jackson, DC; Harrison, LC
    Date
    2003-05-01
    Source Title
    JOURNAL OF CLINICAL INVESTIGATION
    Publisher
    AMER SOC CLINICAL INVESTIGATION INC
    University of Melbourne Author/s
    Jackson, David
    Affiliation
    Microbiology And Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    Martinez, N. R., Augstein, P., Moustakas, A. K., Papadopoulos, G. K., Gregori, S., Adorini, L., Jackson, D. C. & Harrison, L. C. (2003). Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. JOURNAL OF CLINICAL INVESTIGATION, 111 (9), pp.1365-1371. https://doi.org/10.1172/JCI200317166.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/26415
    DOI
    10.1172/JCI200317166
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC154446
    Description

    C1 - Journal Articles Refereed

    Abstract
    Insulin is a major target of the autoimmune response associated with destruction of pancreatic beta 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 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 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 K(d), 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.
    Keywords
    Immunology not elsewhere classified; Infectious Diseases

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