Multiple sclerosis is a chronic demyelinating disease of the human central nervous system. Genetic, viral and autoimmune factors are believed to play a role in the pathogenesis of this disorder. We now propose to investigate the immunoregulatory cells and mechanisms involved in multiple sclerosis by analyzing the proliferative and molecular characteristics of T cell clones specifically reactive against myelin components, in particular, the basic protein of myelin (MBP). Our hypothesis is that idiotypes expressed by autoantigen activated T lymphocytes regulate immune responses through interactions involving anti-idiotypic T cells and anti-idiotypic antibodies. A defect in this complex regulatory network may lead to autoimmune diseases such as multiple sclerosis. First, the response of the T cell clones to the autoantigen will be analyzed with respect to the MBP epitope sepcificity and MHC restriction. Next, we will study the autologous mixed lymphocyte response in nultiple sclerosis patients both at a polyclonal and monoclonal level. The idiotypic nature of anti-MBP T cell lines and clones will be investigated by determining their ability to induce the proliferation of resting autologous T cells (anti-idiotypic T cells). We will then determine the functional nature of the (anti- idiotypic T cells) generated in the reaction. Likewise, we will determine whether sera from patients with multiple sclerosis contain autoantibodies (anti-idiotypic antibodies) which bind anti- MBP clones. The immune abnormalities associated with multiple sclerosis that may be the result of defects in the function of anti- idiotypic autoimmunity will be revealed by these studies. Finally, molecular characterization of selected anti-MBP clones will be carried out by the analysis of the T cell receptor alpha and beta chain gene messages. It is conceivable that a restricted usage of variable region genes of this receptor exists in the T cell response to autoantigens. Identification of the varable region genes used would then provide useful markers for diagnostice and therapeutic purposes. Taken together, the functional, idiotypic and genetic characterization of autoreactive T cell clones should further our understandig of the immune cells and mechanisms involved in multiple sclerosis, and may provide novel means of specific immunological treatment.

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 #
5R29NS025625-02
Application #
3477210
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Bansil, S; Troiano, R; Rohowsky-Kochan, C et al. (1994) Multiple sclerosis: pathogenesis and treatment. Semin Neurol 14:146-53
Rohowsky-Kochan, C; Eiman, D; Denny, T et al. (1994) Induction of autologous mixed lymphocyte culture responses by myelin basic protein-reactive T cell clones. J Neuroimmunol 50:59-70
Rohowsky-Kochan, C; Eiman, D; Cook, S D (1993) Individual specific bias usage of HLA-DR antigens in the restriction of myelin basic protein-reactive T cell clones. J Neurol Sci 117:120-9
Bansil, S; Mithen, F A; Singhal, B S et al. (1992) Elevated neopterin levels in Guillain-Barre syndrome. Further evidence of immune activation. Arch Neurol 49:1277-80
Bansil, S; Mithen, F A; Cook, S D et al. (1991) Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barre syndrome. Neurology 41:1302-5
Bansil, S; Troiano, R; Cook, S D et al. (1991) Serum soluble interleukin-2 receptor levels in chronic progressive, stable and steroid-treated multiple sclerosis. Acta Neurol Scand 84:282-5
Rohowsky-Kochan, C; Eiman, D; Troiano, R et al. (1990) Decreased suppressor-inducer T lymphocytes in multiple sclerosis and other neurological diseases. J Neuroimmunol 28:161-6
Rohowsky-Kochan, C; Troiano, R; Cook, S D (1989) MHC-restricted autoantigen-reactive T cell clones in multiple sclerosis. J Immunogenet 16:437-44