Rheumatoid arthritis is a chronic systemic disease characterized by persistent intense immunologic activity. Recent data have suggested that CD4+ T cells play an essential role in propagating rheumatoid inflammation. Moreover, the data suggest that one abnormality in rheumatoid arthritis is the biased differentiation of IFN-gamma producing Th1 like memory T cells within the synovial compartment. Although synovial T cells are enriched in mature CD4+ CD27- T cells, they contain few, if any, IL-4 producing Th2-like memory cells. This suggests that rheumatoid inflammation might be characterized by an abnormality in the differentiation of IL-4 producing Th2-like cells such that there is persistent unregulated activity of IFN-gamma producing Th1-like memory cells. The proposed experiments will test this hypothesis. In addition, experiments will be carried out to delineate the regulatory events controlling the differentiation of Th l-like and Th2-like cells in patients with rheumatoid arthritis, determine whether abnormalities in the differentiation pathways of these effector T cell subsets are found in patients with rheumatoid arthritis, investigate the impact of synovial influences on these differentiative pathways, and determine whether unique clones of T cells differentiate into cytokine- producing Th1-like memory cells in the rheumatoid synovium. Finally, regulation of the differentiation of Th1 and Th2-like effector cells will be directly analyzed in vivo using rheumatoid synovial tissue engrafted into SCID mice.
The specific aims will be: 1) to examine the capacity of CD4+ T cells from patients with RA to differentiate into IFN-gamma or IL-4 producing Th effector cells; 2) to determine whether features of the rheumatoid synovium influence the development of Th effector cells; and finally 3) to utilize an in vivo model of rheumatoid arthritis, the RA-SCID mouse, to examine the influences on the development of Th effector cells directly. It is anticipated that the information obtained should provide important new insights into the regulatory influences on the differentiation of CD4+ memory effector cells in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045293-04
Application #
6534447
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1999-09-24
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$259,837
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Strauß, Romy; Rose, Thomas; Flint, Shaun M et al. (2017) Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options. J Mol Med (Berl) 95:753-765
Becker, Amy M; Dao, Kathryn H; Han, Bobby Kwanghoon et al. (2013) SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One 8:e67003
Hutcheson, Jack; Scatizzi, John C; Siddiqui, Akbar M et al. (2008) Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 28:206-17
Cravens, P D; Hayashida, K; Davis, L S et al. (2007) Human peripheral blood dendritic cells and monocyte subsets display similar chemokine receptor expression profiles with differential migratory responses. Scand J Immunol 65:514-24
King, Miranda R; Ismail, Anisa S; Davis, Laurie S et al. (2006) Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J Immunol 176:2765-72
Davis, Laurie S; Sackler, Marian; Brezinschek, Ruth I et al. (2002) Inflammation, immune reactivity, and angiogenesis in a severe combined immunodeficiency model of rheumatoid arthritis. Am J Pathol 160:357-67
Brenchley, J M; Douek, D C; Ambrozak, D R et al. (2002) Expansion of activated human naive T-cells precedes effector function. Clin Exp Immunol 130:432-40
Davis, L S; Cush, J J; Schulze-Koops, H et al. (2001) Rheumatoid synovial CD4+ T cells exhibit a reduced capacity to differentiate into IL-4-producing T-helper-2 effector cells. Arthritis Res 3:54-64