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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.

Ling S, Cline EN, Haug TS, Fox DA, Holoshitz J. Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum. 2013;65(3):618-626. PMCID: PMC3582785.

Kato H, Endres J, Fox DA. The roles of IFN-γ versus IL-17 in human Th17 cell pathogenic functions in rheumatoid arthritis. Mod Rheumatol. 2013; 23(6):1140-1150. PMCID: PMC3710715.

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).

Klinker M, Reed T, Fox D, Lundy S. Interleukin-5 supports the growth of Fas ligand-expressing regulatory B cells that induce antigen-specific apoptosis of CD4+ T cells. PLOS One. 2013;8(8). PMCID: PMC3734024.

Chetta M, Burns PB, Kim HM, Burke FD, Wilgis EFS, Fox DA, Chung KC. A Comparative outcomes study of swan-neck versus boutonniere deformity from the Silicone Arthroplasty in Rheumatoid Arthritis (SARA) Study Group. Plast. Reconstr. Surg. 2013;132:597-603.

Gladue HS and Fox DA. Voriconazole-induced periostitis causing arthralgias mimicking a flare of granulomatosis with polyangitis. J Clin Rheumatol, 2013;19(8):444-445.112.

Marchesan JT, Gerow EA, Schaff R, Taut AD, Shin S-Y, Sugai J, Brand D, Burberry A, Jorns J, Lundy SK, Nunez G, Fox DA and Giannobile WV. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis. Arthritis Res Therapy. 2013;15(6):R186.

Kitko C, Levine J, Storer BE, Xiaoyu C, Fox, D, Braun TM, Couriel D, Martin PJ, Flowers ME, Hansen JA, Chang L, Conlon M, Fiema BJ, Morgan R, Pongtornpipat P, Lamiman K, Ferrara JLM, Lee SJ, Paczesny S. Plasma CXCL9 elevations correlate with chronic GVHD diagnosis. Blood, 2014;123(5):786-93.

Klinker MW, Lizzio V, Reed TJ, Fox DA, Lundy SK. Human B cell-derived lymphoblastoid cell lines constitutively produce Fas ligand and secrete MHCII+FasL+ killer exosomes. Front Immunol. eCollection 2014.

Mor-Vaknin N, Saha A, Legendre M, Carmona-Rivera C, Amin MA, Rabquer BJ, Gonzales-Hernandez MJ, Jorns J, Yalavarthi S, Knight J, Adams BS, Koch AE, Fox D, Kaplan MJ, and Markovitz DM. DEK controls the development of neutrophil extracellular traps and modulates inflammation. Submitted 2013.

Sarkar S, Justa S, Brucks M, Shivali J, Brucks M, Endres J, Fox DA, Zhou X, Alnaimat F, Whitaker B, Wheeler JC, Jones BH, Bommireddy SR. IF-17A, F and AF in inflammation: a study in collagen induced arthritis and rheumatoid arthritis. Clin Exp Immunol, 2014 May epub ahead of print.

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, Kummerfeld SK, Holweg CTJ, 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, April 2014 R:90.

Waljee J, Zhong L, Kim HM, Baser O, Yuce H, Fox DA, Chung KC. The incidence of upper extremity surgery for rheumatoid arthritis: a national, population-based longitudinal cohort study. Submitted 2014.

Mukai T, Gallant R, Ishida S, Kittaka M, Yoshitaka T, Fox DA, Morita Y, Nishida K, Rottapel R, Ueki Y. Loss of SH3BP2 function suppresses bone destruction in murine experimental arthritis models. Submitted 2014.

Zhong L, Chung K, Baser O, Fox D, Yuce H, Waljee J. Variation in rheumatoid hand and wrist surgery in the United States: a population – based cohort study. Submitted 2014.

Tsou P-S, Balogh B, Pinney AJ, Zakhem G, Lozier A, Amin MA, Stinson WA, Schiopu E, Khanna D, Fox DA, Koch AE. Lipoic acid plays a role in scleroderma: insights obtained from scleroderma dermal fibroblasts. Arth Res Ther, accepted for publication 2014.

Mukai T, Gallant R, Ishida S, Yoshitaka T, Kittaka M, Nishida K, Fox DA, Morita Y, Ueki Y. SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. PLOS One, submitted 2014.

Fox DA and Holers VM. Special Report: Blue Ribbon Panel on Academic Rheumatology Publishes Final Report. The Rheumatologist, 2013;7(3):16,19.

Fox DA, Holers VM et al. Blue Ribbon Panel Report on Academic Rheumatology. American College of Rheumatology, 2013.

Fox DA and Smith E. Quantitative Production of Monoclonal Antibodies. In: Howard GC, Kaser MR, Eds. Making and Using Antibodies: A Practical Handbook. FL: CRC Press, 2013, p 119-150.

Kim HM, Burns PB, Fox DA, Chung KC, Burke FD, Wilgis EF. Metacarpophalangeal implant surgery: time for a randomized clinical trial? Arthritis Care & Research. 2013;65(6):1014-1015.

Cooney LA and Fox DA. Regulation of Th17 Maturatino by Interleukin 4. Critical Reviews in Immunology, 2013;33(5)379-387.

Cottier KE, Fogle EM, Fox DA, Ahmed S. Noxa in rheumatic diseases: present understanding and future impact. Rheumatology, Dec. 2013. Epub ahead of print

Gizinski AM, Fox DA. T cell subsets and their role in the pathogenesis of rheumatic disease. Current Opinion in Rheumatology, 2014;26(2):204-10.

Gizinski AM, Fox DA. Emerging therapeutic targets: GM-CSF, IL-17and IL-23. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, and Weisman MH, editors. Rheumatology, 6th Edition. Philadelphia, PA. Elsevier Press, 2015:518-521

 


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