David Fox, M.D.
Professor, Department of Internal Medicine
Chief, Division of Rheumatology
dfox@umich.edu

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.

Representative Publications

Yamamura Y, Gupta R, Morita Y, He X, Chung K, Freiberg A, Fox DA. Effector function of resting T cells: Activation of synovial fibroblasts. J Immunol, 166:2270-2275, 2001.

Morita Y, Yang J, Gupta R, Shimizu K, Shelden EA, Endres J, Mule JJ, McDonagh KT, Fox DA. Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. J Clin Invest. 107:1275-1284, 2001

Sarkar S, Tesmer L, Hindnavis V, Endres J and Fox D. IL-17 as a molecular target in immune-mediated arthritis - immunoregulatory properties of genetically-modified dendritic cells that secrete IL-4. Arthritis Rheum, 2007, 50(1)89-100.

Tran C, David M, Tesmer L, Endres J, Motyl C, Smuda C, Somers E, Chung K, Urquhart A, Lundy S, Kovats S, Fox D. Presentation of arthritogenic peptide to antigen specific T cells by fibroblast-like synoviocytes. Arthritis Rheum 2007, 56:1497-1506.

Tran C, White P, Motyl C, Gupta R, Shelden E, Endres J, Chung K, Urquhart A, Fox D. Molecular interactions between T cells and fibroblast-like synoviocytes by T cells is TNFa dependent. Am J Pathol . 2007 Nov; 171 ( 5 ): 1588-98 .

Tran C, Thacker S, Louie D, White P, Endres J, Oliver J, Urquhart A, Chung K, Fox DA. Interactions of T cells with fibroblast-like synoviocytes: Role of the B7 family costimulatory ligand B7-H3. J Immunol, 2008, 180:2989-2998.

Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Imm Reviews 2008, 223: 87-113.

Sarkar S, Cooney LA, White P…Fox DA.  Regulation of pathogenic IL-17 responses in collagen induced arthritis: Roles of endogenous IFN-γ and IL-4.  Arthritis Res Ther, 2009;11(5):R158.

Sabeh F, Fox D, Weiss SJ. MT1-MMP-dependent regulation of rheumatoid arthritis synoviocyte function. J. Immunol. 2010;184(11):6396-6406.

Wallis SK, Cooney LA, Endres J, Lee MJ, Ryu J, Somers E, Fox DA. A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: a possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis. Arth Res Ther. 2011:13(R15).

Cooney LA, Towery KL, Endres J, Fox DA. Sensitivity and resistance to regulation by IL-4 during Th17 maturation. J Immunol. 2011;187(9):4440-50. NIHMS320115.

Wilke CM, Bishop K, Fox D and Zou W. Deciphering the role of Th17 cells in human disease. Trends Immunol. 2011 Dec;32(12):603-11.