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Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity¹

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095

During the development of type I diabetes mellitus in nonobese diabetic (NOD) mice, T cell autoimmunity gradually spreads among cell Ags. Little is known about how autoantigen-based immunotherapies affect this spreading hierarchy. We treated newborn NOD mice with different autoantigenic cell peptides (in adjuvant) and characterized their T cell responses at 4 wk of age, when autoimmunity is usually just beginning to arise to a few cell Ag determinants. Surprisingly, we found that regardless of whether an early, or late target determinant was administered, autoimmunity had already arisen to all tested cell autoantigen determinants, far in advance of when autoimmunity would have naturally arisen to these determinants. Thus, rather than limiting the loss of self-tolerance, immunotherapy caused the natural spreading hierarchy to be bypassed and autoreactivities to develop precociously. Evidently, young NOD mice have a broad array of cell-reactive T cells whose activation/expansion can occur rapidly after treatment with a single cell autoantigen. Notably, the precocious autoreactivities were Th2 type, with the exception that a burst of precocious Th1 responses was also induced to the injected autoantigen and there were always some Th1 responses to glutamic acid decarboxylase. Similarly treated type 1 diabetes mellitus-resistant mouse strains developed Th2 responses only to the injected Ag. Thus, autoantigen administration can induce a cascade of autoimmune responses in healthy (preautoimmune) mice that are merely genetically susceptible to spontaneous autoimmune disease. Such phenomena have not been observed in experimental autoimmune disease models and may have important clinical implications.

This article has been cited by other articles:

				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]

				A. P. Olcott, J. Tian, V. Walker, H. Dang, B. Middleton, L. Adorini, L. Washburn, and D. L. Kaufman Antigen-Based Therapies Using Ignored Determinants of {beta} Cell Antigens Can More Effectively Inhibit Late-Stage Autoimmune Disease in Diabetes-Prone Mice J. Immunol., August 1, 2005; 175(3): 1991 - 1999. [Abstract] [Full Text] [PDF]