Our long term objective has been to elucidate the immunologic mechanisms which are important in the pathogenesis of the autoimmune connective tissue diseases. We have recently made the novel observation that CD8+ lymphocyte subsets from SLE patients paradoxically sustain antibody production. In the next project period, we will determine whether these CD8+ cells found in normal subjects. We will learn whether these cells provide help for B cell activation or are limited to amplifying antibody production by fully differentiated B cells. Using lymphocytes from normal individuals, we will test the hypothesis that up-regulatory effects on antibody production by CD8+ cells reflect an intermediate maturation phase of these cells. This will be accomplished by activating individual CD8+ with monoclonal antibodies against cell surface receptors and determining the conditions which enable them to enhance or suppress antibody production. Signal transduction pathways involved in the generation of regulatory activities will be documented. We will study mobilization of intracellular free calcium and ligand specific activation of protein kinase gained from the study of normal lymphocytes, we will perform comparative studies of CD8+ lymphocytes from SLE patients, family members, discordant twin pairs and normals to determine whether SLE cells are more prone to become amplifiers instead of suppressors. Alternatively, we will determine whether excessive B cell help and impaired suppressor activity result from a deficiency of signals from other cells which are required for the terminal differentiation of CD8+ cells. Elucidation of the specific signals which induce suppression or enhancement and the biochemical mechanisms leading to their regulatory effects in SLE will be most useful in our understanding of the pathogenesis of other chronic inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041768-15
Application #
2667790
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1980-09-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zheng, Song Guo; Wang, Juhua; Wang, Pu et al. (2007) IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178:2018-27
Zheng, Song Guo; Wang, Ju Hua; Stohl, William et al. (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176:3321-9
Horwitz, David A; Zheng, Song Guo; Gray, J Dixon et al. (2004) Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease. Semin Immunol 16:135-43
Zheng, Song Guo; Wang, Ju Hua; Koss, Michael N et al. (2004) CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol 172:1531-9
Zheng, Song Guo; Wang, Ju Hua; Gray, J Dixon et al. (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172:5213-21
Horwitz, David A; Zheng, Song Guo; Gray, J Dixon (2003) The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol 74:471-8
Zheng, Song Guo; Gray, J Dixon; Ohtsuka, Kazuo et al. (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol 169:4183-9
Gray, J D; Liu, T; Huynh, N et al. (2001) Transforming growth factor beta enhances the expression of CD154 (CD40L) and production of tumor necrosis factor alpha by human T lymphocytes. Immunol Lett 78:83-8
Yamagiwa, S; Gray, J D; Hashimoto, S et al. (2001) A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 166:7282-9
Ohtsuka, K; Gray, J D; Quismorio Jr, F P et al. (1999) Cytokine-mediated down-regulation of B cell activity in SLE: effects of interleukin-2 and transforming growth factor-beta. Lupus 8:95-102

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