Glomerulonephritis and small vessel vasculitis caused by antl-neutrophil cytoplasmic autoantibodies (ANCA) is the most common cause for rapidly progressive glomerulonephritis, which frequently leads to end stage renal disease If not diagnosed quickly and treated appropriately. This Project will use mouse models that closely resemble human ANCA disease to advance understanding of the pathogenesis of this autoimmune inflammatory process with the goal of translating this knowledge Into better treatment of patients.
Specific Aim1 will Investigate the role of complement activation and Fcy receptor engagement in mediating ANCA disease. Complement studies will include evaluation of the effects of a novel small molecule inhibitor of human C5a receptor in mice genetically engineered to express human C5a receptor. Involvement of both activating Fcy receptors In Inducing Inflammation, as well as inhibitory Fcy receptors In modulating inflammation will be studies.
Specific Aim 2 seeks to create models of ANCA disease directed at additional autoantigens to more closely parallel human disease. The current model is induced by antibodies to myeloperoxidase.
This Aim will pursue models induced by antibodies to proteinase 3 and lysosomal membrane protein-2;and also will test the ability of complementary (anti-sense) peptides to induce pathogenic autoantibody responses to sense peptides.
Specific Aim 3 will probe the genetic basis for variations in ANCA disease between different strains of mice, which mimics the marked variations in ANCA disease among patients. These studies will utilize a robust new method for genetic research in mice, the Collaborative Cross, which will illustrate the power of this approach for studying kidney diseases. Genes (and their protein products) that are found to influence disease in this animal model will be likely candidates for markers of disease activity and outcome in patients, and might also be logical targets for novel therapies. Investigation of inflammatory and immunologic processes in this animal model will provide insights into other renal and nonrenal inflammatory and autoimmune diseases. The goal of the research is to translate new knowledge from this model into improved outcomes for patients with this aggressive form of kidney disease.

Public Health Relevance

Antlneutrophil cytoplasmic autoantibodies (ANCA) are antibodies that activate inflammatory cells (neutrophils) in the blood causing them to attack small blood vessels in many organs resulting in vascular inflammation (vasculitis). This inflammation often involved the small filtering units of the kidney (glomeruli) resulting in glomerulonephritis. The research in this project will study ANCA disease in experimental animals with the goal of improving treatment for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058335-14
Application #
8566132
Study Section
Special Emphasis Panel (ZDK1-GRB-R)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
14
Fiscal Year
2013
Total Cost
$319,202
Indirect Cost
$103,525
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Aybar, L T; McGregor, J G; Hogan, S L et al. (2015) Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies. Clin Exp Immunol 180:178-88
Cao, Yali; Liu, Kuo; Tian, Zhigang et al. (2015) PTPN22 R620W polymorphism and ANCA disease risk in white populations: a metaanalysis. J Rheumatol 42:292-9
Jennette, J Charles; Falk, Ronald J (2014) B cell-mediated pathogenesis of ANCA-mediated vasculitis. Semin Immunopathol 36:327-38
Joy, Melanie S; Roberts, Brittney V; Wang, Jinzhao et al. (2014) A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis. Int J Clin Pharmacol Ther 52:303-13
Jennette, J Charles; Falk, Ronald J (2014) Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 10:463-73
Xiao, Hong; Dairaghi, Daniel J; Powers, Jay P et al. (2014) C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 25:225-31
Geetha, Duvuru; Poulton, Caroline J; Hu, Yichun et al. (2014) Clinical characteristics and outcome of pauci-immune glomerulonephritis in African Americans. Semin Arthritis Rheum 43:778-83
Xiao, Hong; Ciavatta, Dominic; Aylor, David L et al. (2013) Genetically determined severity of anti-myeloperoxidase glomerulonephritis. Am J Pathol 182:1219-26
Jennette, J Charles (2013) Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 17:603-6
Free, Meghan E; Bunch, Donna O'Dell; McGregor, Julie Anne et al. (2013) Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population. Arthritis Rheum 65:1922-33

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