In this application, we propose to investigate how antigen specific CD4+ T cells mediate glomerular injury, the first key step leading to glomerulonephritis (GN).T cell mechanisms have emerged as potentially the most important mediators in GN. However, antigen specific T cells are largely unanalyzed in existing GN models. It is unknown whether and how antigen specific T cells mediate glomerular injury in GN. Guided by our experience in T cell mediated autoimmune disease we are investigating the roles of T cells specific to autoantigen Col4alpha3NC1, a critical component of glomerular basement membrane, in a rat GN model. We discovered: 1) a 13-mer T cell peptide of Col4alpha3NC1 induced fatal GN similar to human late stage cresentic GN; 2) Col4alpha3NC1 specific CD4+ T cells of TH-1 type transferred severe GN in the naive recipients; 3) transfer of the T cells induced influx of monocytes/T cells into renal cortex. Thus, antigen specific CD4+ T cells may directly mediate glomerular injury and cause GN. Our hypothetical mechanism of glomerular injury mediated by antigen specific CD4+ T cells is as follows: 1. CD4+ T cells specific to autoantigen Col4alpha3NC1 are activated through molecular mimicry by microbial antigens; 2. activated T cells recognize a subpopulation of MHC class II+ glomerular cells; 3. recognition triggers monocytes/T cells influx into glomeruli; glomerular inflammation is initiated and maintained. With our unique model based on Col4alpha3 specific CD4 T cells and the T cell epitope, we will test our hypotheses: 1) We will identify a mimicking T cell peptide from microbial antigens based on the characterization of the 13-mer T cell peptide; 2) We will investigate the antigen presenting capacity of the MHC class II+ glomerular cell subpopulation, which may serve as the target for CD4+ T cells; 3) We will investigate the roles of infiltrating monocytes and T cells in the initiation and maintenance of glomerular inflammation after T cell transfer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK060029-03S1
Application #
6921108
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Flessner, Michael Francis
Project Start
2002-09-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$49,190
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Wu, Jean; Carlock, Colin; Ross, April et al. (2016) CD8??+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats. J Immunol 197:4274-4282
Zhou, Cindy; Lou, Kristie; Tatum, Kiana et al. (2015) Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis. Am J Nephrol 42:42-53
Wu, Jean; Zhou, Cindy; Robertson, Julie et al. (2014) Peripheral blood CD8??+CD11c+MHC-II+CD3- cells attenuate autoimmune glomerulonephritis in rats. Kidney Int 85:1078-90
Zhou, Cindy; Robertson, Julie; Wu, Jean et al. (2011) Natural recovery from antiglomerular basement membrane glomerulonephritis is associated with glomeruli-infiltrating CD8?+CD11c+MHC class II+ cells. Am J Nephrol 34:519-28
Zhou, Cindy; Wu, Jean; Torres, Lisa et al. (2010) Blockade of osteopontin inhibits glomerular fibrosis in a model of anti-glomerular basement membrane glomerulonephritis. Am J Nephrol 32:324-31
Wu, Jean; Zhou, Cindy; Robertson, Julie et al. (2010) Identification of a bone marrow-derived CD8??+ dendritic cell-like population in inflamed autoimmune target tissue with capability of inducing T cell apoptosis. J Leukoc Biol 88:849-61
Merszei, Justin; Wu, Jean; Torres, Lisa et al. (2010) Osteopontin overproduction is associated with progression of glomerular fibrosis in a rat model of anti-glomerular basement membrane glomerulonephritis. Am J Nephrol 32:262-71
Zhou, Cindy; Wu, Jean; Borillo, Jason et al. (2009) Potential roles of a special CD8 alpha alpha+ cell population and CC chemokine thymus-expressed chemokine in ovulation related inflammation. J Immunol 182:596-603
Robertson, Julie; Wu, Jean; Arends, Jon et al. (2008) Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury. J Autoimmun 30:246-56
Arends, Jon; Wu, Jean; Borillo, Jason et al. (2006) T cell epitope mimicry in antiglomerular basement membrane disease. J Immunol 176:1252-8

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