Abstract

Experimental autoimmune encephalomyelitis (EAE) has long been studied as a model for multiple sclerosis. A major focus of research in this model has been the investigation of immunologic mechanisms to suppress the disease process. Oral tolerance is a classic mechanism for the induction of antigen specific peripheral immunologic tolerance, and we have been studying the suppression of the EAE by the oral administration of myelin basic protein (MBP) and myelin antigens. Such studies have direct clinical relevance as there currently are ongoing trials at our institution treating patients with early relapsing remitting multiple sclerosis via oral tolerization to myelin antigens. We have previously shown that oral administration of MBP leads to the generation of CD8+ T cells that adoptively transfer protection and suppress in vitro antigen specific responses. This effect appears to be mediated by an antigen nonspecific factor tentatively identified as TGF-beta which is secreted by CD8+ cells after being triggered by specific antigen.
The specific aims of the revised proposal are as follows: 1) What are the characteristics of the cells involved in suppressing EAE following oral administration of MBP (in vitro studies)? 2) What are the in vivo mechanisms of bystander suppression? 3) What are the in vivo cellular mechanisms involved in generating oral tolerance? 4) Investigation of suppression in the relapsing Lewis rat EAE model and in adoptively transferred EAE.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029352-02
Application #
3416136
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1991-09-30
Project End
1994-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Chen, Y; Hancock, W W; Marks, R et al. (1998) Mechanisms of recovery from experimental autoimmune encephalomyelitis: T cell deletion and immune deviation in myelin basic protein T cell receptor transgenic mice. J Neuroimmunol 82:149-59
Samoilova, E B; Horton, J L; Zhang, H et al. (1998) CTLA-4 is required for the induction of high dose oral tolerance. Int Immunol 10:491-8
Hafler, D A; Kent, S C; Pietrusewicz, M J et al. (1997) Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann N Y Acad Sci 835:120-31
Chen, Y; Inobe, J; Weiner, H L (1997) Inductive events in oral tolerance in the TCR transgenic adoptive transfer model. Cell Immunol 178:62-8
Kent, S C; Fukaura, H; Pietrusewicz, M J et al. (1997) Oral administration of myelin induces antigen-specific TGF-beta 1-secreting T cells in multiple sclerosis patients. Ann N Y Acad Sci 815:412-22
Weiner, H L (1997) Oral tolerance for the treatment of autoimmune diseases. Annu Rev Med 48:341-51
Fukaura, H; Kent, S C; Pietrusewicz, M J et al. (1996) Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 98:70-7
Chen, Y; Inobe, J; Kuchroo, V K et al. (1996) Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci U S A 93:388-91
Hafler, D A; Weiner, H L (1995) Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev 144:75-107
Balashov, K E; Khoury, S J; Hafler, D A et al. (1995) Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis. J Clin Invest 95:2711-9

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