Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that has many features suggesting autoimmune involvement. Experimental allergic encephalomyelitis (EAE) is an autoimmune disease animal model that has many clinical and histopathologic similarities with MS. EAE is mediated by CD4+ Th cells that recognize peptide determinants of myelin basic protein (MBP) or myelin proteolipid protein (PLP) in the CNS and initiate a cascade of events that leads to demyelination and paralysis. The molecular triad consisting of the class II molecule, the peptide target epitope, and the Th cell receptor (TCR) constitute the basic requirements for understanding activation and immunoregulation in autoimmune disease. Intervention of MBP-induced EAE has been achieved with immunospecific therapies aimed at each component of the trimolecular complex. However, recent evidence suggests that PLP may play an important and unique role in immunotherapy of autoimmune encephalomyelitis. Induction of tolerance in SJL/J mice to PLP but not MBP confers resistance to induction of EAE with whole spinal cord. Thus, specific immunotherapy with PLP appears to confer nonspecific protection against challenge with all spinal cord determinants. The recent availability of two distinctly different PLP determinants for SWR/J and SJL/J mice facilitates further studies on immunoregulation of PLP-induced EAE. Our goals in this investigation are: (1) to identify nonencephalitogenic analogues of both PLP determinants, (2) to determine the ability of nonencephalitogenic analogues to compete with the native sequence for class II or TCR binding sites, (3) to determine whether nonencephalitogenic analogues of PLP determinants can prevent EAE induction, and (4) to determine whether restricted TCR gene usage occurs in PLP-induced EAE and whether such restriction could provide a basis for specific immunotherapy. The results of these experiments could lead to a clearer understanding of autoimmune Th recognition and activation and may prove valuable in developing specific immunotherapy in MS once human encephalitogenic determinants are identified.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29NS029095-01
Application #
3478207
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1991-02-01
Project End
1996-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Glabinski, A R; Tuohy, V K; Ransohoff, R M (1998) Expression of chemokines RANTES, MIP-1alpha and GRO-alpha correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation 5:166-71
Yu, M; Johnson, J M; Tuohy, V K (1996) Generation of autonomously pathogenic neo-autoreactive Th1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis. J Neurosci Res 45:463-70
Yu, M; Johnson, J M; Tuohy, V K (1996) A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J Exp Med 183:1777-88
Tani, M; Glabinski, A R; Tuohy, V K et al. (1996) In situ hybridization analysis of glial fibrillary acidic protein mRNA reveals evidence of biphasic astrocyte activation during acute experimental autoimmune encephalomyelitis. Am J Pathol 148:889-96
Yu, M; Nishiyama, A; Trapp, B D et al. (1996) Interferon-beta inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 64:91-100
Glabinski, A R; Tani, M; Aras, S et al. (1995) Regulation and function of central nervous system chemokines. Int J Dev Neurosci 13:153-65
Tuohy, V K; Thomas, D M (1995) Sequence 104-117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. J Neuroimmunol 56:161-70
Tuohy, V K; Thomas, D M; Haqqi, T et al. (1995) Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice. Autoimmunity 21:203-14
Glabinski, A R; Tani, M; Tuohy, V K et al. (1995) Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. Brain Behav Immun 9:315-30
Tuohy, V K; Fritz, R B; Ben-Nun, A (1994) Self-determinants in autoimmune demyelinating disease: changes in T- cell response specificity. Curr Opin Immunol 6:887-91

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