David Fox, MD

From the University of Michigan website:

Research in Dr. Fox's laboratory is directed at defining and characterizing pathways of human T cell activation, and the role of these pathways in the pathogenesis of autoimmune diseases, especially rheumatoid arthritis. One approach has been to develop monoclonal antibodies against T cells to identify new structures and new functions of known structures. Monoclonal antibodies have also been generated against populations with which T cells interact in rheumatoid arthritis, such as synovial fibroblasts (joint lining cells). Through this approach, the CD60 molecule was identified, new functions of CD6 were discovered, and a novel ligand of CD6 was found.

In organ targeted immune-mediated diseases such as rheumatoid arthritis, the interactions between lymphocytes and cells characteristic of the targeted tissue are of special interest. This laboratory has focused extensively on understanding how T cells and synovial fibroblasts interact, and has shown that each cell type activates the other. Synovial fibroblasts can present both superantigens and peptide antigens to T cells, including autoantigens that may be important in the development of arthritis. Conversely, T cells can activate synovial fibroblasts, even in the absence of antigen recognition. The response of fibroblasts to T cells is enhanced by interleukin-17, a cytokine now known to be characteristic of a distinctive effector T cell subset. IL-17 also augments production of CD13 by synovial fibroblasts which, when shed from the cell surface, may be chemotactic for T cells.

Studies in vivo in mice with collagen-induced arthritis, a model system for rheumatoid arthritis, also have shed light on the importance of interleukin-17 producing T cells in joint inflammation. Dr. Fox's laboratory developed a strategy to control collagen arthritis by injection of myeloid dendritic cells transfected with a gene construct that leads to expression of interleukin-4. These genetically modified dendritic cells are potent regulators of the IL-17 response, although TH-17 cells can ultimately become resistant to the effects of IL-4. Current experiments are focusing on the molecular characterization of TH-17 cells that are either sensitive or resistant to immunoregulation. Resistant TH-17 cells might be of special importance in the pathogenesis of chronic immune mediated diseases in humans.