Experimental Autoimmune Encephalomyelitis (EAE) is a demyelinating disease of the CNS which serves as a model for multiple sclerosis (MS) in humans. The disease is mediated by encephalitogenic CD4+ TH1 T cells specific for various myelin proteins which migrate from the periphery to the CNS. Preliminary results from our laboratory suggest that encephalitogenic T cell clones can be anergized in vivo by autologous, genetically manipulated resting B cells expressing specific encephalitogenic determinants. The genetically manipulated B cells survive in the host for long periods and induce long-lasting protection from disease induction in genetically susceptible strains of mice. [The main goals of this proposal are 1) to determine the optimal conditions under which susceptible mouse strains can be effectively protected from passive and active disease induction using a second generation of retroviral vectors and high titer producer lines and 2) developing protocols for the treatment of the chronic relapsing form of EAE which more closely resembles MS. To assess the longevity of the protective effect, cell transfers will be initiated at different time points before disease induction. For the assessment of efficacy in treatment of chronic disease, cell transfers will be started after the first indication of clinical signs or after mice have entered remission. In all cases constitutive expression of the encephalitogenic determinants in the context of MHC class II molecules will be achieved by the inclusion of leader and lysosomal-targeting sequences fused to the encephalitogenic sequence]. Expression of the entire encephalitogenic gene will be compared to expression of a minigene encoding only a single encephalitogenic determinant. Two lines of genetically modified mice will be used to precisely determine the amount of transduced cells required for the efficient induction of T cell unresponsiveness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS038272-02S1
Application #
6415005
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$54,455
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Genetics
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854