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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Winer, S. Articles by Dosch, H.-M. Search for Related Content PubMed PubMed Citation Articles by Winer, S. Articles by Dosch, H.-M.

Peptide Dose, MHC Affinity, and Target Self-Antigen Expression Are Critical for Effective Immunotherapy of Nonobese Diabetic Mouse Prediabetes¹

Shawn Winer^2,*, Lakshman Gunaratnam^2,*, Igor Astsatourov^*, Roy K. Cheung^*, Violetta Kubiak^*, Wolfram Karges^*, Denise Hammond-McKibben^*, Roger Gaedigk^*, Daniel Graziano, Massimo Trucco, Dorothy J. Becker and H.-Michael Dosch^3,*

^* Department of Immunology, University of Toronto, and Immunity, Infection, Injury and Repair Program, The Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada; and Pittsburgh Children’s Hospital, University of Pittsburgh, Pittsburgh, PA 15219

Cross-reactive T cells that recognize both Tep69 (dominant nonobese diabetic (NOD) T cell epitope in ICA69 (islet cell autoantigen of 69 kDa)) and ABBOS (dominant NOD T cell epitope in BSA) are routinely generated during human and NOD mouse prediabetes. Here we analyzed how systemic administration of these mimicry peptides affects progressive autoimmunity in adoptively transferred and cyclophosphamide-accelerated NOD mouse diabetes. These models were chosen to approximate mid to late stage prediabetes, the typical status of probands in human intervention trials. Unexpectedly, high dose (100 µg) i.v. ABBOS prevented, while Tep69 exacerbated, disease in both study models. Peptide effects required cognate recognition of endogenous self-Ag, because both treatments were ineffective in ICA69^null NOD congenic mice adoptively transferred with wild-type, diabetic splenocytes. The affinity of ABBOS for NOD I-A^g7 was orders of magnitude higher than that of Tep69. This explained 1) the expansion of the mimicry T cell pool following i.v. Tep69, 2) the long-term unresponsiveness of these cells after i.v. ABBOS, and 3) precipitation of the disease after low dose i.v. ABBOS. Disease precipitation and prevention in mid to late stage prediabetes are thus governed by affinity profiles and doses of therapeutic peptides. ABBOS or ABBOS analogues with even higher MHC affinity may be candidates for experimental intervention strategies in human prediabetes, but the dose translation from NOD mice to humans requires caution.

This article has been cited by other articles:

				H. Tsui, Y. Chan, L. Tang, S. Winer, R. K. Cheung, G. Paltser, T. Selvanantham, A. R. Elford, J. R. Ellis, D. J. Becker, et al. Targeting of Pancreatic Glia in Type 1 Diabetes Diabetes, April 1, 2008; 57(4): 918 - 928. [Abstract] [Full Text] [PDF]

				R. P. Friday, S. L. Pietropaolo, J. Profozich, M. Trucco, and M. Pietropaolo Alternative Core Promoters Regulate Tissue-specific Transcription from the Autoimmune Diabetes-related ICA1 (ICA69) Gene Locus J. Biol. Chem., January 3, 2003; 278(2): 853 - 863. [Abstract] [Full Text] [PDF]

				S. Winer, I. Astsaturov, R. Gaedigk, D. Hammond-McKibben, M. Pilon, A. Song, V. Kubiak, W. Karges, E. Arpaia, C. McKerlie, et al. ICA69null Nonobese Diabetic Mice Develop Diabetes, but Resist Disease Acceleration by Cyclophosphamide J. Immunol., January 1, 2002; 168(1): 475 - 482. [Abstract] [Full Text] [PDF]

				S. Winer, I. Astsaturov, R. K. Cheung, K. Schrade, L. Gunaratnam, D. D. Wood, M. A. Moscarello, P. O'Connor, C. McKerlie, D. J. Becker, et al. T Cells of Multiple Sclerosis Patients Target a Common Environmental Peptide that Causes Encephalitis in Mice J. Immunol., April 1, 2001; 166(7): 4751 - 4756. [Abstract] [Full Text] [PDF]

				S. Winer, I. Astsaturov, R. K. Cheung, L. Gunaratnam, V. Kubiak, M. A. Cortez, M. Moscarello, P. W. O'Connor, C. McKerlie, D. J. Becker, et al. Type I Diabetes and Multiple Sclerosis Patients Target Islet Plus Central Nervous System Autoantigens; Nonimmunized Nonobese Diabetic Mice Can Develop Autoimmune Encephalitis J. Immunol., February 15, 2001; 166(4): 2831 - 2841. [Abstract] [Full Text] [PDF]