Abstract

Immunoregulatory T cells (Tregs) play an important role in the induction of immune tolerance in autoimmune diseases. This has clearly been shown in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). 3G11 is a molecule that has been identified as a sialylated carbohydrate antigen expressed on a cell membrane disialoganglioside. 3G11 is predominantly expressed on CD4+ T cells. Our preliminary data suggest that the loss of 3G11 is a characteristic of autoantigen-induced Treg cells. At present, this 3G11-CD4+ population is not fully characterized; the origin and mechanisms underlying the generation of these T cells in tolerance are not known; and the relationship between 3G11-CD4+ T cells and other Treg populations, e.g., CD4+CD25+, is not clear. The goal of this proposal is to further characterize and study the mechanisms of action and generation of 3G11-CD4+ T cells in intravenous (i.v.) tolerance. We propose the following Specific Aims: 1)To investigate the mechanism of immunoregulation by 3G11-CD4+ T cells in i.v. tolerance. We have shown that Treg cytokines like IL-10 are involved and we will test the hypothesis that cell-cell contact is also necessary for the function of 3G11- T cells. 2) To determine the mechanisms underlying the generation of 3G11-CD4+ T cells in i.v. tolerance. We will investigate the origin of these cells and test the hypothesis that they are thymus- dependent and further expand in the periphery upon tolerance. 3) To determine the relationship between 3G11-CD4+ T cells and CD4+CD25+ T cells as Tregs. We will test the hypotheses that a) 3G11-CD25+ cells are naturally occurring Tregs, while CD25+3G11+ are non-Treg, activated T cells; b) 3G11-CD25- cells are Tregs induced by i.v. tolerance; and c) FoxpS plays an essential role in the generation of 3G11- Tregs. These studies have the potential to establish a novel surface marker for Tregs, to further enhance our understanding of the mechanisms underlying the generation of these cells, and could lead to the development of novel immunotherapies for autoimmune diseases. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040085-06
Application #
7277620
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Utz, Ursula
Project Start
2000-09-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
6
Fiscal Year
2007
Total Cost
$376,263
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Type
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Li, Hongmei; Gonnella, Patricia; Safavi, Farinaz et al. (2013) Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 254:28-38
Zhou, Fang; Zhang, Guang-Xian; Rostami, Abdolmohamad (2011) 3G11 expression in CD4+ T cell-mediated autoimmunity and immune tolerance. Int Immunopharmacol 11:593-6
Yan, Yaping; Zhang, Guang-Xian; Gran, Bruno et al. (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953-61
Zhao, Zhao; Ciric, Bogoljub; Yu, Shuo et al. (2010) Targeting ganglioside epitope 3G11 on the surface of CD4+ T cells suppresses EAE by altering the Treg/Th17 cell balance. Int Immunol 22:817-26
Xu, Hui; Yan, Yaping; Williams, Mark S et al. (2010) MS4a4B, a CD20 homologue in T cells, inhibits T cell propagation by modulation of cell cycle. PLoS One 5:e13780
Zhao, Zhao; Ciric, Bogoljub; Yu, Shuo et al. (2010) Expression of 3G11 epitope defines subpopulations of regulatory T cells with different suppressive potency. J Neurol Sci 295:66-74
Jiang, Zhilong; Li, Hongmei; Fitzgerald, Denise C et al. (2009) MOG(35-55) i.v suppresses experimental autoimmune encephalomyelitis partially through modulation of Th17 and JAK/STAT pathways. Eur J Immunol 39:789-99
Li, Hongmei; Ciric, Bogoljub; Yang, Jingxian et al. (2009) Intravenous tolerance modulates macrophage classical activation and antigen presentation in experimental autoimmune encephalomyelitis. J Neuroimmunol 208:54-60
Li, Hongmei; Zhang, Guang-Xian; Chen, Youhai et al. (2008) CD11c+CD11b+ dendritic cells play an important role in intravenous tolerance and the suppression of experimental autoimmune encephalomyelitis. J Immunol 181:2483-93
Zhao, Zhao; Yu, Shuo; Fitzgerald, Denise C et al. (2008) IL-12R beta 2 promotes the development of CD4+CD25+ regulatory T cells. J Immunol 181:3870-6

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