David Fox, M.D.

Professor, Department of Internal Medicine
Chief, Division of Rheumatology

Biography

Dr. Fox received his undergraduate degree from the Massachusetts Institute of Technology (1970-1974), and his M.D. degree from Harvard Medical School (1974-1978).  Following training in Internal Medicine and Rheumatology at the Brigham and Women's Hospital (1978-1982), he pursued a Research Fellowship with Drs. Stuart Schlossman and Ellis Reinherz at the Dana-Farber Cancer Center (1982-l985) in the area of human T cell activation.  He was appointed Assistant Professor in the Division of Rheumatology at the University of Michigan in 1985, and was promoted to Associate Professor and Division  Chief in 1990 and Professor in 1995.  He also serves as Director of the Hybridoma Core facility for the University of Michigan Medical School, and is Director of the University of Michigan Clinical Autoimmunity Center of Excellence, funded by the NIH.

Dr. Fox's research focuses on defining and characterizing pathways of human T cell activation, determining the role of these pathways in the pathogenesis of autoimmune disease, investigating T cell interactions with synovial fibroblasts, understanding pathways of inflammation in arthritic joints, and understanding the role of interleukin-17 in arthritis. He is also studying the pathogenesis and treatment of scleroderma. He is author of more than 200 scientific papers and book chapters and has served on the Editorial Board of Arthritis & Rheumatism and as an Associate Editor of the Journal of Immunology and the Journal of Clinical Investigation. He is a member of the American Society for Clinical Investigation and the Association of American Physicians.

In 2007-2008, Dr. Fox served as the seventy-first President of the American College of Rheumatology and the sixth ACR President from the University of Michigan

Research Interests

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, is chemotactic for T cells, monocytes and endothelial 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. Other experiments focus 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. 

Recently, Dr. Fox’s lab has also begun to study the role of T cells in scleroderma and new approaches to treating scleroderma.

Publications

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, 56(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, Lundy S, White P, Endres J, Motyl C, Gupta R, Wilke C, Shelden E, Chung K, Urquhart A, Fox D. Molecular interactions between T cells and fibroblast-like synoviocytes: role of membrane TNFα on cytokine-activated T cells.  Am J Pathol, 2007;171(5):1588-1598.

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.Sarkar S, Cooney LA, White P, Dunlop DB, Endres J, Jorns JM, Wasco MJ, 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. PMC2787258.

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

Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Venkataraman S, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178).

Haak A, Tsou P-S, Amin M, Ruth J, Campbell P, Fox D, Khanna D, Larsen S, Neubig R. Targeting the myofibroblast genetic switch: inhibitors of MRTF/SRF-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharm Exp Ther. 2014; 349(3):480-6.

Dennis, Jr. G, Holweg CT, Kummerfeld SK, Choy D, Setiadi AF, Hackney JA, Haverty PM, Gilbert H, Lin WY, Diehl L, Fischer S, Song A, Musselman D, Klearman M, Gabay C, Kavanaugh A, Endres, Fox DA, Martin F, Townsend MJ. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Research &  Therapy. 2014;16(2):R:90.

Morgan R, Endres J, Behbahani-Nejad N, Phillips K, Friday SC, Lanigan T, Urquhart A, Chung KC, and Fox DA. Expression and function of aminopeptidase N/CD13 produced by fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2015;67(1):74-85.

Tsou PS, Amin MA, Campbell PL, Zakhem G, Balogh B, Edhayan G, Ohara RA, Schiopu E, Khanna D, Koch AE, Fox DA.Activation of the Thromboxane A2 Receptor by 8-Isoprostane Inhibits the Pro-Angiogenic Effect of Vascular Endothelial Growth Factor in Scleroderma.J Invest Dermatol. 2015 Dec;135(12):3153-62.