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Thomas A. Wynn, Ph.D.

Photo of Thomas A. Wynn, Ph.D. 

Chief, Immunopathogenesis Section
Laboratory of Parasitic Diseases
Scientific Director, NIH Oxford-Cambridge Scholars Program

Major Areas of Research

  • Type-2 immunity and wound repair
  • Asthma and idiopathic pulmonary fibrosis
  • Liver fibrosis
  • Intestinal fibrosis in inflammatory bowel disease
  • Stem cells and tissue regeneration

Program Description

The focus of the Immunopathogenesis Section (IPS) is on understanding the immunological and molecular mechanisms of fibrosis. The ultimate goal is to identify a first-in-class therapy for fibrotic diseases, for which no viable therapeutic strategy currently exists. The IPS research program relies heavily on transgenic and knockout mouse models to dissect the mechanisms of fibrosis and focuses on three major organs systems including the liver, lung, and gastrointestinal tract. We also utilize a variety of human cells in vitro and have recently established clinical protocols, which are allowing us to translate our experimental findings to better understand the mechanisms of fibrosis in humans.

Arginase-1-expressing macrophages function as suppressor cells during helminth infection. Mice deficient in Arginase-1 in macrophages (Arg1-/flox; LysMcre) fail to downregulate the egg-induced inflammatory response when chronically infected with Schistosoma mansoni. The Arg1-/flox; LysMcre also develop severe liver fibrosis, as shown here by second harmonic emission confocal microscopy. The image shows extensive collagen deposition around schistosome eggs lodged in the liver (see Pesce et al., doi:10.1371/journal.ppat.1000371).
Credit: NIAID

Fibrosis is the final common pathological outcome of many chronic infections and inflammatory diseases. Although synthesis of extracellular matrix components like collagen is an indispen­sable and, typically, reversible part of all wound healing reactions, normal tissue repair can evolve into a progressively irreversible fibrotic response if the tissue injury is severe or repetitive or if the wound-healing response itself becomes dysregulated. Fibrosis is defined by the excessive accu­mulation of fibrous connective tissue (components of the extracel­lular matrix [ECM] such as collagen and fibronectin) in and around inflamed or damaged tissue, which leads to permanent scarring, organ malfunction, and ultimately death, as seen in end-stage liver disease, idiopathic pulmonary fibrosis (IPF), and heart failure. Fibrosis is also a major pathological feature of many chronic autoimmune diseases, including Crohn’s disease, ulcerative colitis, scleroderma, rheumatoid arthritis, myelofibrosis, and systemic lupus erythematosus. Fibrosis also contributes to tumor invasion and metastasis, chronic graft rejection, and the pathogenesis of many progressive myopathies. Although fibrogenesis is increasingly recog­nized as a major cause of morbidity and mortality, there are few—if any—treatment strategies that specifically target the mechanisms of fibrosis, despite the fact that nearly 45 percent of all deaths in the developed world are attributable to progressive fibroproliferative disease.

The IPS has focused on fibrosis since its inception, with a major emphasis on the mechanisms of liver fibrosis induced during infection with the helminth parasite Schistosoma mansoni. In early studies, we showed that liver fibrosis correlates with the development of the type-2 immune response and that IL-12 and IFN-γ, cytokines associated with type-1 immunity, play inhibitory roles. Consequently, our research program has focused heavily on elucidating the contribution of the type-2 response in the initiation, maintenance, and resolution of fibrosis in schistosomiasis and related fibrotic diseases. Although we have had a strong interest in the mechanisms that initiate type-2 responses during helminth infection, much of our research has focused on the downstream effector response that is activated by IL-4 and IL-13, including mediators like IL-10, Arginase-1, Relm-alpha, acidic mammalian chitinase (AMCase), BRB-39, periostin, and IL-13Rα2, with the primary goal of elucidating their roles in fibrosis. As we were the first group to demonstrate a central and indispensable role for IL-13 in the development of fibrosis, a large part of our program continues to focus on IL-13 biology, with particular emphasis on the role of the IL-13 signaling and decoy receptors. Identifying the key cellular targets of IL-13 has also been emphasized in our research, as we hypothesize that any intervention that disrupts critical steps in the IL-13 response might emerge as a viable therapeutic strategy for fibrosis.

Specific aims of the IPS include the following:

  • Identify common and unique mechanisms of fibrosis in various organ systems and/or diseases, including persistent asthma, idiopathic pulmonary fibrosis, liver fibrosis, and inflammatory bowel disease
  • Characterize the IL-13 pathway of fibrosis and elucidate the function of novel downstream target genes that are regulated by Th2-associated cytokines
  • Understand the link between inflammatory mediators like IL-1, TNF-alpha, and IL-17 and pro-fibrotic cytokines like TGF-beta and IL-13 in various murine models of fibrosis
  • Elucidate the role of monocyte and macrophage subsets in wound healing, chronic inflammation, and fibrosis progression and resolution
  • Investigate the therapeutic potential of induced pluripotent stem cells in fibrosis
  • Translate findings from mice to humans by establishing relevant preclinical models of fibrosis, so that novel therapies for liver fibrosis and other chronic fibroproliferative disorders might be evaluated quantitatively, in vivo, over time

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Dr. Wynn is a senior investigator and chief of the Immunopathogenesis Section of the Laboratory of Parasitic Disease. He also serves as the scientific director of the NIH Oxford-Cambridge Scholars program, a doctoral training program for outstanding science students committed to biomedical research, which annually supports more than 52 doctoral candidates at NIH, Oxford University, and Cambridge University. Dr. Wynn obtained his Ph.D. from the University of Wisconsin-Madison Medical School in the department of microbiology and immunology. His laboratory group uses a variety of in vivo model systems to study the immunological mechanisms controlling chronic inflammation and fibrosis. He has published over 175 papers, reviews, and book chapters in many prestigious journals, including Nature, Nature Immunology, Journal of Experimental Medicine, Gastroenterology, Nature Reviews Immunology, Nature Medicine, and Annual Review of Immunology. He has made seminal contributions to our understanding of the role of IL-13, IL-17A, and macrophages in the progression and resolution of liver and lung fibrosis and has developed in vivo models to test novel anti-fibrotic drugs. Dr. Wynn was recently elected to fellowship in the American Academy of Microbiology and has received several prestigious awards, including the Bailey K. Ashford Medal from the American Society of Tropical Medicine and Hygiene, the Oswaldo Cruz Medal from the Oswaldo Cruz Foundation, and two Merit Awards from NIH. Dr. Wynn has organized several national and international scientific meetings, including three Keystone Symposia, and collaborates extensively with the pharmaceutical industry.

Research Group

Photo of LPD group members
L to R back row: Kevin Vannella, Sandy White, David Cantu, Rob Thompson, and Josh Sciurba
Middle row: Trisha Pasricha, Luke Barron, Trey Gieseck, and Kevin Hart
Front row: Tom Wynn, Casey Rimland, Nikhil Jiwrajka, and Thiru Ramalingam

Selected Publications

Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease.. Nature. 2013 Apr 25;496(7446):445-55.

Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012 Jul 6;18(7):1028-40.

Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011 Oct 19;12(11):1035-44.

Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011 Oct 14;11(11):723-37.

Wilson MS, Ramalingam TR, Rivollier A, Shenderov K, Mentink-Kane MM, Madala SK, Cheever AW, Artis D, Kelsall BL, Wynn TA. Colitis and intestinal inflammation in IL10-/- mice results from IL-13Rα2-mediated attenuation of IL-13 activity. Gastroenterology. 2011 Jan;140(1):254-64.

Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010 Mar 15;207(3):535-52.

Visit PubMed for a complete publication list.

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Last Updated August 19, 2015