Cytokines suppress experimental allergic encephalomyelitis (EAE), a rodent model of central nervous system (CNS) autoimmune disease. This proposal is based on differential CD4+ T cell responses induced in EAE susceptible female and EAE resistant young adult (6 wk) male SJL mice. Female susceptibility is consistent with the increased prevalence of a number of human autoimmune diseases including multiple sclerosis, myasthenia gravis, rheumatoid arthritis and SLE. Thus, the gender-based difference in CD4+ T cell responsiveness in SJL mice provides a unique opportunity to explore in vivo suppression of Th1 cell mediated CNS autoimmune disease via Th2 cells using a single mouse strain. Co-transfer of myelin basic protein (MBP)-specific Th1 effectors and MBP-specific Th2 cells has a dramatic inhibitory effect on both acute and relapse EAE compared to recipients of Th1 effectors only. Similarly, co-transfer of MBP specific Th1 EAE effectors and Th2 cells specific for a non-neuroantigen (Ag) also has a dramatic inhibitory effect on acute and relapse EAE, albeit only in the presence of Ag. The overall goal of this proposal is to define the mechanism(s) of Th2 mediated EAB suppression. Our global hypothesis is that Th2 mediated suppression of CNS autoimmune disease reflects induction of a regulatory/suppressor population of CD4+ T cells, designed Tr cells. A potential role of TGF-Beta in addition to IL- 10, in mediating Th2 induced EAE inhibition is examined. This proposal uses Thy1.1/ThyI .2 disparate donors and recipients, in addition to a recently developed SJL TcR transgenic mouse. Analysis of these donor/recipient combinations, using both in vitro analysis and adoptive transfer of purified populations to inhibit EAE will define the precise phenotype of the effector cells. The issue of derivation of Tr cells is critical to understanding both their biology and therapeutic potential. Therefore, we will determine if the effectors are derived from the donor Th2 population or from the host. Although activated Th1 cells access the CNS, little is known concerning recruitment and/or retention of Tr cells at the site of autoimmunity. Adoptive transfer of effectors derived from either congenic Thy1.1 SJL or Thy1.2 TcR transgenic mice into Thy1 disparate recipients, coupled with analysis of CNS infiltrating cells will determine CNS entry. Mechanism(s) of acute EAE suppression will be examined by determining: 1) the effects of disease inhibition on macrophage influx into the CNS; 2) alterations in the ability of CNS antigen presenting cells to support encephalitogenic Th1 T cells; and 3) the potential activation of neuroAg-specific host derived Th2 cells in the altered CNS environment. Mechanisms of relapse inhibition examined include; 1) CNS retention of effector cells; 2) continued expression of IL- 10 by potential CNS APC populations inhibiting activation of host derived encephalitogenic Th1 cells; 3) activation and retention of neuroAg specific Th2 cells specific for encephalitogenic or nonencephalitogenic epitopes, or 4) inhibition of epitope spreading associated with relapses in SJL mice. These experiments will provide information on both the mechanisms of induction of these important regulatory cells, which are critical to both regulation and suppression of autoimmune disease, as well as on their specific role(s) in suppressing CNS autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035085-08
Application #
6769409
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
1996-04-01
Project End
2006-06-30
Budget Start
2004-07-15
Budget End
2005-07-14
Support Year
8
Fiscal Year
2004
Total Cost
$308,750
Indirect Cost
Name
University of Southern California
Department
Neurology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Dowdell, Kennichi C; Cua, Daniel J; Kirkman, Erlinda et al. (2003) NK cells regulate CD4 responses prior to antigen encounter. J Immunol 171:234-9
Cua, D J; Stohlman, S A (1997) In vivo effects of T helper cell type 2 cytokines on macrophage antigen-presenting cell induction of T helper subsets. J Immunol 159:5834-40