Experimental allergic encephalomyelitis (EAE) in the SJL/J strain mouse has been intensively studied as protypical model of human multiple sclerosis. Although there is a great deal known about the role of autoreactive T cells in the induction of EAE in genetically susceptible mice, little is known about the predisposing events that are responsible for the generation and function of these abnormal T cells. The purpose of this proposal is to test the hypothesis, partly suggested by our preliminary data, that the T cell abnormalities in EAE result from intrinsic defects in prothymocytes and/or the thymic microenvironment. Specifically, we will attempt to answer the following questions: 1) Can the predisposition to acute (A) and chronic-relapsing (CR) EAE be transferred to naive recipients by SJL/J prothymocytes? 2) Does the thymic microenvironment contribute to the generation of autoreactive T cells in SJL/J mice? 3) Do other host factors also predispose SJL/J mice to EAE? 4) Does the presence, absence or imbalance of certain functional T cell subsets render SJL/J mice susceptible to EAE? 5) Can prothymocytes or the thymus from normal, genetically EAE-resistant mice render SJL/J mice resistant to EAE? We will use a quantitative adoptive transfer system between EAE-susceptible SJL/J (H-2s, Thy 1.2) and EAE-resistant B10.S (H-2s, Thy 1.1) mice to determine whether SJL/J prothymocytes can transfer the predisposition for the development of A-EAE and CR-EAE to naive B10.S recipients. Reciprocal prothymocyte transfer and thymus grafting experiments between SJL/J and B10.S mice will be used to test the possible role of intra- and extra-thymic environmental factors in determining EAE susceptibility or resistance. Prothymocyte mixing (competition) experiments will provide in vivo evidence for the role of modulator T cells in promoting or inhibiting EAE. The possible role of accessory cells in predisposing SJL/J mice to EAE will also be assessed in cell transfer experiments. In addition, we will trace the generation of EAE-specific functional T cell subsets (effector, suppressor, contrasuppressor) by SJL/J and B10.S prothymocytes. For this purpose, sensitized T cells of donor and host origin will be separated from the above chimeras according to their Thy 1 alloantigenic phenotypes, subfractionated according to their Lyt 2 phenotypes (Lyt 2+ or Lyt 2-), and tested for their ability to influence the blastogenic response to basic myelin protein in vitro and to induce or prevent the development of EAE in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021536-02
Application #
3402725
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
School of Medicine & Dentistry
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030