Rheumatoid arthritis (RA) is a crippling disease afflicting millions of people worldwide. Its progressive, destructive pathology significantly affects mobility and quality of life. RA is a complex disease process that involves the interaction of HLA molecules and immune cells that results in synovial inflammation, cartilage and bone destruction, and loss of joint function. Although its etiology is still a mystery, it is clear that there is a strong association between susceptibility to RA and the HLA genes that mediate immune responses, suggesting an autoimmune basis for the disease. Regulatory T cells (Tregs) are a newly described subset of suppressive cells that are absolutely critical for immune homeostasis. Without a proper compliment of Tregs, multiple forms of autoimmunity develop quickly. It is clear that Tregs can modulate autoimmunity, but there are large gaps in our understanding of how Tregs function in vivo, and how they can be manipulated for the development of new therapeutic approaches to the treatment of autoimmune diseases. We will use a Foxp3gfp/IL-17Frfp dual reporter readout in the context of our well- characterized animal model for arthritis to give us a unique opportunit to dissect the role of Treg cells in autoimmunity, allowing us to directly examine the ability of these cells to regulate an autoimmune response and we can directly measure how these manipulations can prevent disease pathology. Our research to date has suggested that parenteral exposure of the vertebrate immune system to a soluble antigen supplied without co-stimulation can result in an activation and expansion of a pre-existing population of regulatory T cells. It is our hypothesis that this activation provides the commitment necessary to prevent the possible conversion of these nTregs into Th17 cells upon subsequent exposure to their cognate ligand under pro-inflammatory conditions such as those found in the rheumatoid joint. We propose to use both in vitro and in vivo models to determine the mechanism(s) by which parenteral antigen induced immunoregulation prevents the development of the Th17 cell response, thereby providing protection from the debilitating joint pathologies characteristic of RA. We will also determine if the proper stimulation of Tregs can prevent them from converting to Th17 cells in the presence of pro-inflammatory mediators. Successful elucidation of the answers to these problems will allow us to design cell-based therapeutic treatments for those veterans suffering from the debilitating effects of RA and other inflammatory autoimmune diseases.

Public Health Relevance

This is a research project that experimentally determines the roles played by regulatory T cells (Tregs) in regulating the development of inflammatory arthritis. Lineage, mechanism of action and phenotypic and functional stability are addressed.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001193-04
Application #
8965959
Study Section
Immunology A (IMMA)
Project Start
2012-10-01
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Memphis VA Medical Center
Department
Type
DUNS #
078577285
City
Memphis
State
TN
Country
United States
Zip Code
38103
Yang, Sujuan; Wang, Julie; Brand, David Douglass et al. (2018) Role of TNF-TNF Receptor 2 Signal in Regulatory T Cells and Its Therapeutic Implications. Front Immunol 9:784
Tamaddon, M; Burrows, M; Ferreira, S A et al. (2017) Monomeric, porous type II collagen scaffolds promote chondrogenic differentiation of human bone marrow mesenchymal stem cells in vitro. Sci Rep 7:43519
Thirunavukkarasu, Shyamala; Khan, Nayaab S; Song, Chi Young et al. (2016) Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice. Am J Pathol 186:2204-2219
Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet et al. (2016) 6?-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice. Hypertension 67:916-26
Sandal, Indra; Karydis, Anastasios; Luo, Jiwen et al. (2016) Bone loss and aggravated autoimmune arthritis in HLA-DR?1-bearing humanized mice following oral challenge with Porphyromonas gingivalis. Arthritis Res Ther 18:249
Deng, Nan; Jiao, Yan; Cao, Yanhong et al. (2014) Genomic locus on chromosome 1 regulates susceptibility to spontaneous arthritis in mice deficiency of IL-1RA. BMC Immunol 15:57
Meyers, Lindsay; Groover, Chassidy J; Douglas, Joshua et al. (2014) A role for Apolipoprotein A-I in the pathogenesis of multiple sclerosis. J Neuroimmunol 277:176-85
Tamaddon, M; Walton, R S; Brand, D D et al. (2013) Characterisation of freeze-dried type II collagen and chondroitin sulfate scaffolds. J Mater Sci Mater Med 24:1153-65