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 Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR029846-11
Application #
3155710
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1980-09-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
11
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
Ohtsuka, K; Gray, J D; Stimmler, M M et al. (1999) The relationship between defects in lymphocyte production of transforming growth factor-beta1 in systemic lupus erythematosus and disease activity or severity. Lupus 8:90-4
Horwitz, D A; Gray, J D; Ohtsuka, K (1999) Role of NK cells and TGF-beta in the regulation of T-cell-dependent antibody production in health and autoimmune disease. Microbes Infect 1:1305-11
Horwitz, D A; Gray, J D; Behrendsen, S C et al. (1998) Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus. Arthritis Rheum 41:838-44
Gray, J D; Hirokawa, M; Ohtsuka, K et al. (1998) Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3. J Immunol 160:2248-54
Ohtsuka, K; Gray, J D; Stimmler, M M et al. (1998) Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 160:2539-45
Horwitz, D A; Gray, J D; Ohtsuka, K et al. (1997) The immunoregulatory effects of NK cells: the role of TGF-beta and implications for autoimmunity. Immunol Today 18:538-42
Gray, J D; Horwitz, D A (1995) Activated human NK cells can stimulate resting B cells to secrete immunoglobulin. J Immunol 154:5656-64
Horwitz, D A; Jacob, C O (1994) The cytokine network in the pathogenesis of systemic lupus erythematosus and possible therapeutic implications. Springer Semin Immunopathol 16:181-200
Stohl, W; Elliott, J E; Wang, H et al. (1994) Enhancing effects of interleukin 2-treated peripheral blood mononuclear cells on subsequent B cell differentiation. Cell Immunol 157:381-92

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