Great strides have been made in the treatment of Antl-Neutrophil Cytoplasmic Autoantibody (ANCA) - associated glomerulonephritis and small vessel vasculitis (ANCA disease). However major challenges remain In the form of mortality, and Irreversible organ damage, elevated rates of disease relapse and significant risks of severe adverse effects from current conventional therapy. New concepts have recently emerged from In vitro and animal studies that pertain to the mechanisms by which ANCA are induced, and those detailing their role in the vascular Injury leading to glomerulonephritis and vasculitis. Our group has introduced strong evidence in support of (1) the important role of complement activation in the pathogenesis of ANCA disease in the mouse model, (2) epigenetic dysregulation leading to aberrant expression of the leukocyte myeloperoxidase and PRS genes as a possible mechanism of disease relapse, and (3) protein complementarity as a trigger to autoimmunity to proteinase 3 (PR3) and plasminogen. The newly discovered antlplasmlnogen antibodies inhibit fibrin degradation and are hypothesized to contribute to the increased risk of thromboembolic event seen In patients with ANCA disease. The ultimate test of relevance of these new concepts lies in their applicability to human disease. The overall goal of this project is to test the impact of our advances on the treatment of ANCA disease through novel approaches to therapy. We will do so through two proof of concept, interventional, open label, randomized and controlled clinical trials.
Specific Aim 1 will test the novel concept of inhibiting complement activation in patients with active de novo or relapsing disease using the monoclonal antibody to complement factor C5, Ecullzumab (Sollris?) as an adjunct to conventional induction therapy.
Specific Aim 2 will test the concept of modulating autoantigen gene expression on the course of disease using all-trans retinoic acid (tretinoin) as an adjunct to conventional maintenance therapy in patients with mild or moderate disease activity. In a screening cohort study, Specific Aim 3 will test the impact of the anti-plasminogen autoantibodies on the detection and risk of thromboembolic events, a well recognized complication of ANCA disease.

Public Health Relevance

Several findings emerged from our laboratory and animal studies that fundamentally alter our understanding of the mechanisms of ANCA disease. In this project, we will test their applicability to patient treatment in 2 proof of concept clinical trials using FDA-approved agents. We will also test the impact of the newly identified, anti-plasminogen antibodies on the occurrence of clotting complications of ANCA disease. The novel therapeutic concepts developed in this project may extend to other autoimmune diseases.

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 #
8566133
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
$204,267
Indirect Cost
$66,249
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

Showing the most recent 10 out of 42 publications