This proposal presents an opportunity to lean more about genetic resistance to autoimmune neural tissue destruction. This study was prompted by an observation of clinical and histopathologic resistance to the induction of Experimental Allergic Encephalomyelitis (EAE) in a colony of Lewis (designated Le-R) rats. A subline of Le-R rats, in which greater than 99% of the population is EAE-resistant, was established by selective breeding. Other breeding experiments between Lewis (Le) and Le-R rats indicated that, at 7-8 weeks of age, resistance is a dominant, autosomal trait possibly mediated by only one or two genes. In contrast to EAE-resistant Brown Norway rats, Le-R rats develop cellular reactivity, as assessed by macrophage migration inhibition, for the critical disease-inducing determinant located within an encephalitogenic peptide derived from the myelin basic protein molecule. Although Le-R spleen cells failed to transfer disease to naive Le rats, Le-R recipients were susceptible to passive disease induction mediated by in vitro conditioned, sensitized Le spleen cells. These observations suggest that resistance is expressed during the development of disease-inducing effector cells from specific antigen-reactive cells. The experiments presented in this proposal are designed to investigate the resistance mechanism: 1) Is resistance immunologic? 2) Is resistance mediated by a mechanism similar to that of other EAE-resistant animals? Question 1 will be approached by constructing chimeras in which Le-R immune systems will be implanted into lethally irradiated Le rats. Question 2 will be approached by determining if mechanisms which mediate resistance in other EAE-resistant animals are operative in Le-R rats. The ultimate long-term goal of this project is to identify the Le-R gene(s) that mediates resistance, and to decipher its mechanism of action. This may be useful in developing immunotherapeutic approaches for treating human neurological diseases such as multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019563-03
Application #
3399655
Study Section
Neurology A Study Section (NEUA)
Project Start
1983-12-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210