Monocyte-T cell interactions are key events in mediation of pathologic immune responses. The broad objectives of this project are to study roles that T cells and monocytes play in rheumatoid arthritis (RA), by focusing on the roles that CD44 isoforms and CD7 deficient T cells play in the pathogenesis of RA and in animal models of inflammatory synovitis. These objectives will be accomplished by the use of peripheral blood (PB), synovial fluid (SF) and synovial tissue from patients with RA, as well as evaluation of a series of novel CD44 and CD7 deficient mouse strains for their ability to develop synovitis when injected with challenge antigens or when bred to mice susceptible to HTLV-l tax transgenic mouse arthritis.
Specific aims for Project l are as follows: l) We will study the roles of cytokines in vivo and in vitro in regulation of hyaluronan (HA) binding to CD44 isoforms on monocytes and other synovial cell types in RA, and in tax transgenic mice and mice with collagen-induced arthritis. Study of the cytokines that regulate HA binding (and therefore HA-induced proinflammatory events) in RA and in animal models of RA-like synovitis are critical to development of novel interventional strategies for treatment of RA. 2) We will define the roles of CD44 isoforms in inflammatory synovitis using: a) total CD44 deficient mice. b) mice selectively deficient only in variant CDT forms (but expressing the standard CD44 form. CD44S), and c) mice only expressing select variant CD44 isoforms. CD44 deficient mice will be studied for their response to antigen-induced arthritis (AIA). and bred on a HTLV-l tax transgenic background to determine the effect of CD44 selective and total deficiencies on arthritis in HTLV- l tax transgenic mice. 3) We will study the roles of CD7 deficient T cells and an altered TCR repertoire in mediation of inflammatory synovitis by isolating CD4+, CD7-, CD28- T cells from RA and OA PBMC. SF and synovial tissue and determining the ability of these T cells to produce IFN-gamma and other cytokines/chemokines in response to T cell activation signals, and by studying CD7 deficient mice, in the presence and absence of abnormal T cell receptor (TCR) repertoires in TCR transgenic mice, for their ability to develop arthritis. Taken together these studies will provide insight into the roles that T cells and monocytes play in inflammatory synovitis. and provide new targets for novel therapeutic interventions in RA.
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