HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Olcott, A. P. Articles by Kaufman, D. L. Search for Related Content PubMed PubMed Citation Articles by Olcott, A. P. Articles by Kaufman, D. L.

Antigen-Based Therapies Using Ignored Determinants of Cell Antigens Can More Effectively Inhibit Late-Stage Autoimmune Disease in Diabetes-Prone Mice¹

Angelica P. Olcott^*, Jide Tian^*, Valerie Walker^*, Hoa Dang^*, Blake Middleton^*, Luciano Adorini, Lorraine Washburn^* and Daniel L. Kaufman^2,*

^* Department of Molecular and Medical Pharmacology, University of California, School of Medicine, Los Angeles, CA 90095; and BioXell, Milan, Italy

As organ-specific autoimmune diseases do not become manifest until well-advanced, interventive therapies must inhibit late-stage disease processes. Using a panel of immunogenic peptides from various cell Ags, we evaluated the factors influencing the efficacy of Ag-based therapies in diabetes-prone NOD mice with advanced disease. The ability of the major cell autoantigen target determinants (TDs) to prime Th2 responses declined sharply between 6 and 12 wk of age, whereas the ability of immunogenic ignored determinants (IDs) of cell Ags to prime Th2 responses was unaffected by the disease process. The different patterns of TD and ID immunogenicity (even from the same cell Ag) may be due to the exhaustion of uncommitted TD-reactive, but not ID-reactive, T cell pools by recruitment into the autoimmune cascade. Therapeutic efficacy was associated with a peptide’s immunogenicity and ability to promote Th2 spreading late in the disease process but not its affinity for I-Ag⁷ or its expression pattern ( cell specific/nonspecific or rare/abundant). Characterization of some IDs revealed them to be "absolute" cryptic determinants. Such determinants have little impact on T cell selection, leaving large precursor T cell pools available for priming by synthetic peptides. Traditional Ag-based therapeutics using whole autoantigens or their TDs cannot prime responses to such determinants. These findings suggest a new strategy for designing more efficacious Ag-based therapeutics for late-stage autoimmune diseases.

This article has been cited by other articles:

				S. M. Pop, C. P. Wong, Q. He, Y. Wang, M. A. Wallet, K. S. Goudy, and R. Tisch The Type and Frequency of Immunoregulatory CD4+ T-Cells Govern the Efficacy of Antigen-Specific Immunotherapy in Nonobese Diabetic Mice Diabetes, May 1, 2007; 56(5): 1395 - 1402. [Abstract] [Full Text] [PDF]

				J. Tian, D. Zekzer, Y. Lu, H. Dang, and D. L. Kaufman B Cells Are Crucial for Determinant Spreading of T Cell Autoimmunity among beta Cell Antigens in Diabetes-Prone Nonobese Diabetic Mice J. Immunol., February 15, 2006; 176(4): 2654 - 2661. [Abstract] [Full Text] [PDF]