Thomas A. Wynn, Ph.D.
Chief, Immunopathogenesis Section
Senior Investigator
Immunopathogenesis Section
Description of Research Program
Research in the Immunopathogenesis Section is focused on understanding the molecular and immunological mechanisms regulating the pathogenesis of schistosomiasis and other chronic fibrotic diseases.
Tissue fibrosis or scarring is a leading cause of morbidity and mortality worldwide. Current health statistics suggest that almost 45% of all deaths in the western world are attributed to some type of chronic fibrotic disease. Fibrosis affects nearly all tissues and organ systems. Diseases in which fibrosis is a major cause of morbidity and mortality include the interstitial lung diseases, liver cirrhosis, kidney disease, heart disease, systemic sclerosis, among others. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients.
Current treatments for fibrotic disorders target the inflammatory cascade, but they have been largely unsuccessful, primarily because the mechanisms that are involved in fibrogenesis are believed to be distinct from those involved in inflammation.
In murine schistosomiasis, the pathology resulting from infection with Schistosoma mansoni is predominantly caused by the host reaction to parasite eggs that are laid in the portal venous system and subsequently trapped in the liver and intestine. Egg induced liver fibrosis can lead to portal hypertension, which causes much of the morbidity and mortality associated with the disease. A major emphasis of our research program has been to dissect the contributions of type 1 (IFN gamma, IL-12) and type 2 associated cytokines (IL-4, IL-5, IL-10, and IL-13) to the pathogenesis of schistosomiasis-induced liver fibrosis. An important discovery by our group was the finding that type-2-associated cytokines are critical mediators of fibrosis, with IL-13 being particularly important.
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(View larger image)
Picrosirius red staining of collagen (red) around granulomas in liver chronically infected with Schistosoma mansoni. Mice with targeted deletion of the IL-13 receptor alpha 2 develop uncontrolled inflammation and hepatic fibrosis following infection, while in IL-13-deficient animals, fibrosis is ablated. |
In experiments conducted with a soluble IL-13 antagonist, we showed that IL-13 plays an indispensable role in the fibrotic process. In contrast, IFN-gamma, IL-12, IL-10, and the IL-13 decoy receptor (IL-13R alpha-2) appear to antagonize the pro-fibrotic effects of IL-13. An important objective of our research will be to determine whether IL-13 antagonism can be developed as a strategy to treat chronic fibrotic disease and to fully characterize the molecular pathway of IL-13 mediated fibrogenesis.
Little information exists regarding the regulation of fibrosis by type-2 cytokines; therefore, a major effort of our research program in the coming years will be to exploit emerging technologies such as gene and protein microarray technologies to further characterize this unique and important feature of the type-2 response. We hope that better understanding of the molecular mechanism(s) of fibrosis will significantly improve our understanding of disease processes in general, and ultimately translate into a successful intervention strategy for schistosomiasis and other chronic fibrotic disorders.
We are always looking for enthusiastic new investigators to join our group so if you are interested, please feel free to contact me to learn more about the latest research going on in the Immunopathogenesis Section of the LPD.
Research Group Members
Lab members from left to right, top to bottom: Allen Cheever (inset photo), Jessica Lue (summer student), John Pesce, Margaret Mentink-Kane, Robert Thompson, Thiru Ramalingam, Tom Wynn, Mark Wilson
Selected Recent Publications
(View list in PubMed.)
Ramalingam TR, Pesce JT, Sheikh F, Cheever AW, Mentink-Kane MM, Wilson MS, Stevens S, Valenzuela DM, Murphy AJ, Yancopoulos GD, Urban JF Jr, Donnelly RP, Wynn TA. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat Immunol. 2008 Jan;9(1):25-33. Epub 2007 Dec 9.
Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008 Jan;214(2):199-210.
Wilson MS, Elnekave E, Mentink-Kane MM, Hodges MG, Pesce JT, Ramalingam TR, Thompson RW, Kamanaka M, Flavell RA, Keane-Myers A, Cheever AW, Wynn TA. IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. J Clin Invest. 2007 Oct;117(10):2941-51.
Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007 Mar;117(3):524-9.
Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF, Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest. 2006.Jul;116(7):2044-55. Epub 2006 Jun 15.
Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004 Aug;4(8):583-94.
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