Several lines of evidence argue that T cell-mediate autoimmunity plays a role in the pathogenesis of multiple sclerosis (MS). The precise nature of the antigen eliciting the autoimmune attack on the myelin sheath is not known, but in-vivo-activated, clonally expanded lymphocytes reactive with myelin basic protein (MBP) have been demonstrated in MS peripheral blood. Injection of MBP into susceptible strains of mice together with immunologic adjuvants results in the induction of experimental autoimmune encephalomyelitis (EAE), a chronic relapsing disease with extensive demyelination. EAE, induced by CD4+ cells of the Th1 type, is viewed as the best model currently available for testing of MS therapeutic regimens. We have reported that the oral administration of MBP exerts a profoundly suppressive effect on EAE in Lewis rats. Rats fed MBP exhibit a striking inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, and suppressed T and B cell responses specific for MBP. Two mechanisms have been put forward to explain orally induced tolerance in the EAE model - clonal anergy and active suppression. In applying oral tolerance to the treatment of chronic disease like MS, it will be necessary to determine whether an ongoing autoimmune process can be suppressed after initiation of immunologic injury. We have obtained preliminary data indicating that orally administered MBP, given either before challenge or at the time of disease onset, is acute effective in suppressing relapses of EAE. Therefore, with our background in the oral tolerance field and new preliminary data relative to chronic, relapsing disease, we propose to address several aims relative to our underlying hypothesis that oral tolerance is mediated through clonal anergy or deletion and is capable of halting the progression of ongoing autoimmune disease. First, we will determine the relative efficacy of oral neuroantigen administration in relapsing EAE. In these studies, we will focus on the specificity of tolerance and the timing of tolerogen administration relative to disease using whole neuroantigens (MBP, PLP, myelin). Effectiveness of these neuroantigens at the time of disease appearance, or during a remission period or at the time of relapse will be tested. Second, we will determine the fine specificity of oral tolerance in the B10.PL mouse using MBP Peptides. Tolerogenicity of encephalitogenic as well as non- encephalitogenic peptides and MBP peptide analogs will be studied. Third, the mechanism(s) of suppression of relapsing EAE will be studied by examining suppressor T cells, clonal anergy, clonal deletion, and shifts in cytokine profile as possible candidates. These studies will be aided by the availability of a Valpha2/VBeta8.2 transgenic mouse. Therefore, at the conclusion of these experiments, the boundaries of the oral tolerance therapeutic approach in its alteration of the long-term course of a chronic inflammatory disease will be defined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035960-04
Application #
2330418
Study Section
Special Emphasis Panel (SRC (25))
Project Start
1994-05-01
Project End
1999-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
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
Whitacre, Caroline C; Song, Fei; Wardrop 3rd, Richard M et al. (2004) Regulation of autoreactive T cell function by oral tolerance to self-antigens. Ann N Y Acad Sci 1029:172-9
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
Benson, J M; Campbell, K A; Guan, Z et al. (2000) T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen. J Clin Invest 106:1031-8
Dowdell, K C; Gienapp, I E; Stuckman, S et al. (1999) Neuroendocrine modulation of chronic relapsing experimental autoimmune encephalomyelitis: a critical role for the hypothalamic-pituitary-adrenal axis. J Neuroimmunol 100:243-51
Benson, J M; Stuckman, S S; Cox, K L et al. (1999) Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis. J Immunol 162:6247-54
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

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