Although the etiology of multiple sclerosis (MS) is unknown, one of the central theories regarding its pathogenesis involves autoimmunity specific for myelin antigens. Experimental autoimmune encephalomyelitis (EAE), induced by myelin basic protein (MBP) and adjuvant, is studied as a model for MS since the two disease share clinical, histopathologic, and immunologic features. We have recently reported that the oral administration of MBP renders Lewis rats refractory to EAE. MBP-fed rats exhibit a profound decrease in clinical neurologic signs, significantly lessened CNS histopathologic changes, absent lymphocyte proliferative responses to MBP, and decreased serum anti-MBP antibody. We have accumulated much evidence supporting a profound reduction in MBP-reactive lymphocytes in orally tolerant rats. The goals of this application are the determination of whether MBP-reactivity lymphocytes are silenced in tolerant rats by clonal deletion, clonal anergy or an alteration in trafficking; the examination of the role of the intestinal epithelium in tolerance induction; the definition of the fine specificity of tolerance at the peptide level, and the applicability of this approach to an ongoing, chronic inflammatory process. Specifically, we propose: To examine mucosal and peripheral lymphoid tissues and the CNS for the presence of functional MBP-reactive T lymphocytes. These studies will utilize limiting dilution analysis (LDA) to detect IL-2 secreting MBP-specific T cells. Also, we propose To examine mucosal and peripheral lymphoid tissues and the CNS for the presence of lymphocytes containing mRNA for the MBP-specific T cell receptor. These studies, performed in collaboration with Dr. Ellen Heber-Katz, will employ northern analysis and address the question of whether specific MBP-reactive lymphocytes are deleted/inactivated or re- located in tolerant animals. Next, we propose To determine whether MBP- induced oral tolerance can be reversed by treatment of tolerant lymphocytes with IL-2, thus distinguishing between deletion and anergy mechanisms. Then, we will Examine a possible role for intestinal epithelial cells in the induction of oral tolerance to MBP since these cells constitutively express Ia, may lack costimulatory activity and are located at a critical position for contacting orally introduced antigen. Next, we propose To elucidate the fine specificity of MBP-induced tolerance by the oral administration of a nested series of peptides. We have shown that the 68- 88 peptide is tolerogenic when administered orally. These studies are directed at determining the minimal tolerogenic peptide within that region as well as the epitope specificity of oral tolerance. Finally, we propose To determine if the course of chronic relapsing EAE can be altered by the oral administration of MBP. These studies will use the mouse model of chronic relapsing EAE testing the therapeutic efficacy of oral MBP begun at various times throughout the disease course. Therefore, the ability of this therapeutic strategy, viz., orally administered myelin antigens, to alter the long-term course of a chronic inflammatory process such as MS can be tested.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023561-07
Application #
2264880
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1986-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1996-03-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Song, Fei; Wardrop, Richard M; Gienapp, Ingrid E et al. (2008) The Peyer's patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomylelitis (EAE). J Autoimmun 30:230-7
Song, Fei; Gienapp, Ingrid E; Wang, Xianming et al. (2002) Activation of Vbeta8 T cells affects spontaneous EAE in MBP TCR transgenic mice. J Neuroimmunol 123:112-22
Song, Fei; Wardrop, Richard M; Gienapp, Ingrid E et al. (2002) Differences between two strains of myelin basic protein (MBP) TCR transgenic mice: implications for tolerance induction. J Autoimmun 18:27-37
Meyer, A L; Benson, J; Song, F et al. (2001) Rapid depletion of peripheral antigen-specific T cells in TCR-transgenic mice after oral administration of myelin basic protein. J Immunol 166:5773-81
Goldman-Brezinski, S; Brezinski, K; Zhang, X M et al. (1998) Effects of oral tolerance induction by myelin basic protein on Vbeta8+ Lewis rat T cells. J Neurosci Res 51:67-75
Jewell, S D; Gienapp, I E; Cox, K L et al. (1998) Oral tolerance as therapy for experimental autoimmune encephalomyelitis and multiple sclerosis: demonstration of T cell anergy. Immunol Cell Biol 76:74-82
Benson, J M; Whitacre, C C (1997) The role of clonal deletion and anergy in oral tolerance. Res Immunol 148:533-41
Javed, N H; Gienapp, I; Cox, K et al. (1996) Oral tolerance in experimental autoimmune encephalomyelitis: specificity of peptide-induced oral tolerance. Ann N Y Acad Sci 778:393-4
Meyer, A L; Benson, J M; Gienapp, I E et al. (1996) Suppression of murine chronic relapsing experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. J Immunol 157:4230-8
Whitacre, C C; Gienapp, I E; Meyer, A et al. (1996) Treatment of autoimmune disease by oral tolerance to autoantigens. Clin Immunol Immunopathol 80:S31-9

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