The overall theme of the Program project outlined in this application is the genetics, cytokine regulation and inflammatory cell migration into rheumatoid synovium of an autoimmune arthritis, induced by systemic immunization of mice with cartilage proteoglycan (aggrecan). This proteoglycan (aggrecan)-induced arthritis (PGIA) shows many similarities to human rheumatoid arthritis (RA) as indicated by clinical assessments such as radiographic analyses, scintigraphic bone scans and various functional tests, and by histopathologic studies of diarthrodial joints. The development, and then the progressivity, of this RA-like disease is based upon autoimmune reactions which develop against the mouse (self) cartilage proteoglycan. Arthritis develop only in genetically susceptible BALB/c mice or their F2 hybrids. It is accompanied with inflammatory cell migration into the joint, mediated by Th1 type cytokines. We combined three research projects in one program to utilize a very unique condition of accumulated information and experience of investigators. Project 1 will identify non-MHC-linked loci int he mouse genome which harbor genes responsible for proteoglycan arthritis, and then to identify these genes by positional cloning. Project 2 will evaluate the function and balance of Th1 and Th2 cytokines, manipulate the Th1 cytokine dominance in pre-arthritic stage of the disease and explore the mechanisms as how the anti-inflammatory cytokines suppress inflammation in synovium. In addition, this project will perform preventive studies in SCID mice using human synovium and anti- inflammatory cytokines. Gene therapeutic approaches for delivery of Th2 cytokines in a site-specific fashion. Project 3 will study the function of CD44 in inflammatory cell migration and the different aspects of anti-CD44 treatment, and what the conditions of receptors of receptor shedding are in vitro and in vivo. This project will also utilize human synovium (normal or arthritic) in SCID mice to delineate how CD44 expression might be controlled by intracellular events (signal transduction). Each of the projects are highly integrated with each other and centered around a unique theme and supported by two Cores.