Systemic lupus erythematosus (SLE) affects millions of people in the United States. Development of SLE is multi-factorial, including both genetic and environmental influences. Fas and FasL genes are critical regulators involved in SLE development by inducing death of activated lymphocytes. A single defect in either gene causes lethal SLE-like disease. Although the general scheme of Fas-based mechanism is widely accepted, the intricate interactions among various components of the immune system remain largely unexplored. Understanding these molecular mechanisms will be crucial for future development of better prevention and treatment of SLE. Ulcerative colitis is an inflammatory bowel disease (IBD) that, like SLE, has genetic elements and environmental factors for its development. Studies of II-2 and II-2Ralpha gene knockout mice reveal an interesting association of several immune-based diseases with the gene defects. These mice develop""""""""autoimmune-like"""""""" disease characterized by a mild lymphadenopathy, infiltration of lymphocytes into several organs, autoimmune hemolytic anemia and ulcerative colitis. Two major hypotheses have been proposed. One believes that IL-2 is critical for the induction of lymphocyte death by regulating apoptosis-promoting and apoptosis-preventing molecules. The second hypothesis proposes that IL-2 is regulating CD25+CD4 + regulatory T cells that are critical to the containment of autoimmune response. Despite no simple treatment can cure these diseases, we have been able to cure both diseases-induced end organ failure and lethality in animal models by using genetic approach. When we bred the fas mutant gene into the IL-2 knockout recipients, the lethality imposed by either gene was inhibited. We hypothesize that IL-2 is the most important lymphokine required for the development of autoimmune lymphocytes in Ipr mice and that Fas-mediated apoptosis is critical for the life-threateninq end-orqan patholoqy of the ulcerative colitis. In these protected mice, there are numerous interesting phenotypes that have implications in the development of the disease, their participating components, and their mechanisms of action. The goals of the application are to prove the hypothesis and to further understand the regulatory mechanisms responsible for the protection a0ainst the mutant gene-imposed lethality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051203-04
Application #
7385081
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$311,753
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Chan, Derek V; Sharma, Rahul; Ju, Chiao-Ying A et al. (2013) A recombinant scFv-FasLext as a targeting cytotoxic agent against human Jurkat-Ras cancer. J Biomed Sci 20:16
Sharma, Rahul; Sung, Sun-Sang J; Gaskin, Felicia et al. (2012) A novel function of IL-2: chemokine/chemoattractant/retention receptor genes induction in Th subsets for skin and lung inflammation. J Autoimmun 38:322-31
Ju, Shyr-Te; Sharma, Rahul; Gaskin, Felicia et al. (2012) IL-2 controls trafficking receptor gene expression and Th2 response for skin and lung inflammation. Clin Immunol 145:82-8
Sharma, Rahul; Fu, Shu Man; Ju, Shyr-Te (2011) IL-2: a two-faced master regulator of autoimmunity. J Autoimmun 36:91-7
Sharma, Rahul; Sharma, Poonam R; Kim, Young-Chul et al. (2011) IL-2-controlled expression of multiple T cell trafficking genes and Th2 cytokines in the regulatory T cell-deficient scurfy mice: implication to multiorgan inflammation and control of skin and lung inflammation. J Immunol 186:1268-78
Sharma, Rahul; Sung, Sun-Sang J; Ju, Chiao-Ying A et al. (2011) Regulatory T-Cell (Treg) hybridoma as a novel tool to study Foxp3 regulation and Treg fate. J Autoimmun 37:113-21
Sharma, Rahul; Ju, Shyr-Te (2010) Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin Immunol 136:162-9
Sharma, Rahul; Sung, Sun-sang Joe; Fu, Shu Man et al. (2009) Regulation of multi-organ inflammation in the regulatory T cell-deficient scurfy mice. J Biomed Sci 16:20
Kinsey, Gilbert R; Sharma, Rahul; Huang, Liping et al. (2009) Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol 20:1744-53
Sharma, Rahul; Sung, Sun-sang Joe; Abaya, Christian E et al. (2009) IL-2 regulates CD103 expression on CD4+ T cells in Scurfy mice that display both CD103-dependent and independent inflammation. J Immunol 183:1065-73

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