This is an application for the continuation of a Program Project Grant (""""""""Autoimmune Arthritis: Genetics and Cellular Regulation"""""""") at Rush-Presbyterian-St. Luke's Medical Center, Chicago. The overall theme of the continuation of this Program Project outlined in this application is the genetics, cytokine/chemokine regulation, T cell signaling and inflammatory cell migration into joints in an autoimmune arthritis, induced by systemic immunization of mice with cartilage proteoglycan (aggrecan). This proteoglycan-induced arthritis (PGIA) shows many similarities to human rheumatoid arthritis and may serve as a prototype of the human disease. Arthritis develops only in genetically susceptible BALB/c mice and in a few C3H colonies, and their F2 hybrids. This polygenic disease exhibits a recessive inheritance and makes this model system more superior than any other routine model of arthritis. The development of the disease is accompanied with inflammatory cell migration into the joints, antigen-driven mechanisms are mediated by Th1-type cytokines, and associated with altered T cell functions. The current period of research identified 26 genetic (Pgia) loci in this model, including at least 10 overlapping genetic loci with other models and a number of human autoimmune diseases; including rheumatoid arthritis. We combined four research projects in one program to utilize a very unique condition of accumulated information and experience of investigators. Project by Glant will confirm the pathological role of the most critical non-MHC-linked loci in the disease mechanisms and reduce the size of these chromosome regions to be suitable for detailed genetic analysis. Project by Finnegan will study the role of novel and previously identified Th1 factors (cytokines, transcription factors, cytokine/chemokine receptors, adhesion molecules) that synergistically control susceptibility to PGIA. This project will also identify the target cell population(s) regulated by IL-4 and IFN-y that controls onset and severity in arthritis. Project by Zhang (new) will investigate whether and how IL-4, a Th2 cytokine, regulates T cell function including activation-induced T cell apoptosis, T cell proliferation, Th1 vs. Th2 cell development, and cell cycle progression in autoimmune arthritis. Better understanding of the biological function of IL-4 will shed light on the development of novel therapeutic approaches to autoimmune arthritis. Finally, Project by Mikecz will study the mechanisms by which the major adhesion molecules, CD44 and L-selectin, control leukocyte extravasation into the joints of mice with PGIA. The traffic of inflammatory cells to arthritic joints will be monitored directly by intravital microscopy, a novel method recently established in our laboratory. The role of CD44 and L-selectin in arthritis will be investigated using gene knockout mice, and biologic agents that antagonize CD44 and selectin function, and thus prevent inflammatory cell extravasation. The four projects are supported by two core facilities: (i) Animal, Genotyping, Cell and Tissue (AGCT) Core and (ii) Administrative and Statistics Core.
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