Autoimmune anti-GBM glomerulonephritis (GN) is currently incurable.
We aim to elucidate pathogenesis of this disease, which may lead to development of a novel therapeutic strategy. In our rat model for anti-GBM GN, LEW rats spontaneously recover from early inflammation. Observations on this naturally occurring recovery mechanism had led to our working hypothesis for the current grant: A novel glomeruli- infiltrating CD8 + DC (GIL CD8 + DC) terminated autoimmune damage in glomeruli by inducing apoptosis in self-reactive T cells through antigen presentation;failure in this mechanism led to uncontrolled glomerular damage as seen in GN-susceptible WKY rats. In the past 3 years, we have verified our hypothesis. First, we demonstrated that GIL CD8 + DC induced apoptosis in T cells by its intracellular Fas-L. Second, timely infiltration of GIL CD8 + DC into glomeruli was decisive for the recovery. Third, we delineated the lineage of GIL CD8 + DCs and identified its precursor in PBL. Most importantly, transfer of PBL precursor of GIL CD8 + DCs of LEW rats cured GN in GN-susceptible WKY rats. Thus, defects in GIL CD8 + DCs are responsible for GN in WKY rats. In addition, our preliminary data suggested that defect in expression of several leukocyte- trafficking related molecules in precursor of GIL CD8 + DCs in WKY rats may be responsible for the delay. Thus, mimicking this natural recovery mechanism in rats may lead to a potential immunotherapy for human autoimmune GN. We hypothesize that timely expression of leukocyte trafficking related molecules in both GIL CD8 + DC and inflamed glomeruli governs timely infiltration. This renewal application will investigate how the CD8 + DCs timely infiltrate glomeruli with emphasis on leukocyte trafficking related molecules in both PBL CD8 + precursor and inflamed glomeruli in Aims 1 and 3. We will further test if enhancing the cell's ability in timely infiltration through genetic manipulation will cure GN in GN-susceptible WKY rats (Aim 2). Accomplishment of those aims will not only reveal a unique immune tolerance mechanism occurring in the target organ, but also provide a working model for development of cell-based immunotherapy for autoimmune GN.

Public Health Relevance

Autoimmune anti-GBM glomerulonephritis is currently incurable. A rat strain shows spontaneous recovery from this disease. We aim to elucidate why a novel CD8 + DC-like cell is critical for the recovery, and further to test if mimicking this natual recovery mechanism can be applied for a cell-based immunotherapy for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK077857-04A1S1
Application #
8598160
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2007-04-01
Project End
2016-03-31
Budget Start
2013-02-25
Budget End
2013-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$14,186
Indirect Cost
$4,853
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) CD8αα+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; Carlock, Colin; Zhou, Cindy et al. (2015) IL-33 is required for disposal of unnecessary cells during ovarian atresia through regulation of autophagy and macrophage migration. J Immunol 194:2140-7
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
Carlock, Colin I; Wu, Jean; Zhou, Cindy et al. (2014) Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J Immunol 193:161-9
Carlock, Colin; Wu, Jean; Zhou, Cindy et al. (2013) Ovarian phagocyte subsets and their distinct tissue distribution patterns. Reproduction 146:491-500
Zhou, Cindy; Robertson, Julie; Wu, Jean et al. (2011) Natural recovery from antiglomerular basement membrane glomerulonephritis is associated with glomeruli-infiltrating CD8ýý+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 CD8αα+ 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

Showing the most recent 10 out of 12 publications