The objective has been to characterized immunoregulatory abnormalities in patients with connective tissue diseases. Our studies originally focused on a subset of human blood lymphocytes with high density Fc receptors for IgG which we called """"""""L cells."""""""" These lymphocytes are part of a larger population characterized by a unique morphological appearance and which react with monoclonal antibodies which recognize the Type III complement receptor (CR3). We plan to separate L cells and other CR3+ lymphocyte subsets, determine their relationship with T cells and determine their regulatory effects on B cell activity in patients with Systemic Lupus Erythematosus. We have recently observed that lymphocytes from patients with both active and inactive SLE have an impaired capacity to produce interleukin 2 in vitro. Moreover, these patients have spontaneously activated T8+ lymphocytes that inhibit IL-2 production. We plan to determine whether this is an inherited, primary immunologic defect in SLE or whether it is a secondary manifestation of the disease. This will be accomplished by a study of Twins with SLE. Our last objective is to determine the relationship of the IL-2 defect and B lymphocyte hyperactivity in SLE. This will be accomplished by determining the effects of interleukin 2 on lymphocytes which regulate the production of B cell growth factors and which have direct effects on B cell functions. We will determine whether CR3+ lymphocytes are involved in these regulatory circuits. These studies should lead to a better understanding of pathogenetic mechanisms in patients with the connective tissue diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR029846-08
Application #
3155708
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1980-09-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1990-06-30
Support Year
8
Fiscal Year
1988
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
90033
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
Gray, J D; Hirokawa, M; Horwitz, D A (1994) The role of transforming growth factor beta in the generation of suppression: an interaction between CD8+ T and NK cells. J Exp Med 180:1937-42
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

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