Many autoimmune diseases, such as colitis and arthritis, are caused by inflammatory mediators such as TNF. Great strides have been made in treating these disorders by using drugs that neutralize TNF. While effective, there are side effects such as increased susceptibility to infections and cancer. Further progress in treatment could be made by selectively targeting the pathogenic cells that induce inflammation. Many of these diseases were thought to be caused by Th1 cells, which promote an inflammatory environment. More recently, it has become recognized that Th17 cells also play an important role in the pathogenesis of these diseases. Our preliminary data indicate that blocking the Fyn tyrosine kinase, results in Th17 cells that make little IL- 17. Furthermore a higher proportion of cells express Foxp3, a marker of immunosuppressive Treg cells. T cell mediated colitis is strongly delayed when using Fyn deficient T cells, suggesting that interfering with Fyn function may be a novel target for treating Th17 mediated diseases.
Aim 1 will characterize the mechanism by which fyn-/- T cells cause less severe colitis by determining whether the Foxp3+ Tregs are functional and if there is reduced IL-17 with disease.
Aim 2 will focus on determining whether pharmacologic inhibition of Fyn and other Src kinases in vivo can delay or reverse colitis. These experiments will help provide insight into whether constant inhibition of Fyn is needed to maintain the Foxp3+ cells and reduced IL17 or whether transient inhibition is sufficient to maintain the unusual TH17 cells that have elevated Foxp3 and reduced IL17. A goal of these studies is to better understand how the signaling pathways controlling Th17/Treg development are regulated. Not only will this greatly enhance our understanding of the pathogenesis associated with the inappropriate differentiation of Th17 cells, it will also suggest novel approaches to treat disease. When these studies are completed we will have established a potentially novel pathway by which Th17 cells are controlled.

Public Health Relevance

Many inflammatory diseases are now believed to be caused by the development of a T cell subset termed Th17. Production of IL-17 by these cells helps promote synthesis of other inflammatory cytokines as well as attracting neutrophils, which can cause tissue damage. We have uncovered a novel pathway regulating the function of Th17 cells, where the Fyn kinase appears to control the ability to synthesize IL-17 and regulate production of Treg cells, an immunosuppressive lineage that are closely related to TH17 cells. Understanding how Th17 cells are regulated may provide a unique avenue for developing the next generation of therapeutics for inflammation present in a variety of diseases such as IBD and psoriasis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Rothermel, Annette L
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Sri International
Menlo Park
United States
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