FoxP3+ regulatory T cells play critical roles in maintaining immune tolerance in the intestine. FoxP3+ regulatory T cells migrate not only to the intestine but also to other organs for regulation of immune responses. The mechanisms that direct the migration of FoxP3+ T cells to the intestine and their specificity for the intestine versus other organs are largely unknown. This is a significant problem in developing FoxP3+ T cells into cellular therapeutics specifically targeting inflammatory diseases of the intestine. The objective of this application is to devise strategies by which we can generate gut-homing FoxP3+ T cells specific for normal or inflamed intestine. The central hypothesis of this application is that migration of FoxP3+ T cells to normal and inflamed intestine can be controlled by regulating the expression of gut-homing receptors in FoxP3+ T cells. Our rationale is that it will become possible to more effectively prevent or suppress inflammatory diseases in the intestine by regulating the migration of FoxP3+ T cells to normal or diseased intestine after the proposed research is completed. Also, it will be possible to increase the specificity of FoxP3+ T cells for inflammatory diseases in the intestine but reduce the side effect of the regulatory T cell therapy on necessary immune responses to pathogens or cancer cells in other organs. We propose the following aims to validate the hypothesis and accomplish the goal.
Specific aim #1 : Determine the temporal and spatial origin of gut- homing FoxP3+ T cells;
Specific aim #2 : Establish strategies to generate FoxP3+ regulatory T cells that preferentially migrate to intestine versus other organs;
Specific aim #3 : Establish strategies to generate FoxP3+ regulatory T cells that target inflamed tissue sites within the intestine. As the outcome, we will have the FoxP3+ T cells tailor-made for normal intestine to prevent inflammation or for inflamed intestine to suppress established inflammation. Once the strategy is validated by the proposed studies, it can be applied also to specific suppression of diseases at other tissue sites. Relevance to Public Health: The research will provide strategies for generation of FoxP3+ regulatory T cells that can specifically target normal or inflamed intestine and effectively prevent or suppress inflammation. Therefore, the proposed research will have positive impacts on prevention and control of inflammatory diseases in the intestine. In addition, the outcomes will have far-reaching implications for treatment of other chronic inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076616-05
Application #
8230608
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Hamilton, Frank A
Project Start
2008-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$290,179
Indirect Cost
$94,159
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Kim, Myunghoo; Kim, Chang H (2016) Colonization and effector functions of innate lymphoid cells in mucosal tissues. Microbes Infect 18:604-614
Kim, Myunghoo; Qie, Yaqing; Park, Jeongho et al. (2016) Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host Microbe 20:202-14
Kim, Chang H; Hashimoto-Hill, Seika; Kim, Myunghoo (2016) Migration and Tissue Tropism of Innate Lymphoid Cells. Trends Immunol 37:68-79
Park, Jeongho; Goergen, Craig J; HogenEsch, Harm et al. (2016) Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell-Mediated Ureteritis and Hydronephrosis. J Immunol 196:2388-400
Kim, Chang H (2015) A functional relay from progesterone to vitamin D in the immune system. DNA Cell Biol 34:379-82
Kim, Myung H; Taparowsky, Elizabeth J; Kim, Chang H (2015) Retinoic Acid Differentially Regulates the Migration of Innate Lymphoid Cell Subsets to the Gut. Immunity 43:107-19
Park, J; Kim, M; Kang, S G et al. (2015) Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8:80-93
Thangamani, Shankar; Kim, Myughoo; Son, Youngmin et al. (2015) Cutting edge: progesterone directly upregulates vitamin d receptor gene expression for efficient regulation of T cells by calcitriol. J Immunol 194:883-6
Kim, Chang H; Hashimoto-Hill, Seika; Kang, Seung G (2015) Human Tfh and Tfr cells: identification and assessment of their migration potential. Methods Mol Biol 1291:175-86
Kim, Chang H; Park, Jeongho; Kim, Myunghoo (2014) Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immune Netw 14:277-88

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