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 #
5P01DK058335-13
Application #
8566058
Study Section
Special Emphasis Panel (ZDK1-GRB-R (M1))
Project Start
2000-09-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$214,214
Indirect Cost
$69,475
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Mariani, Laura H; Pendergraft 3rd, William F; Kretzler, Matthias (2016) Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology. Clin J Am Soc Nephrol 11:2054-2060
Yang, Jiajin; Ge, Heng; Poulton, Caroline J et al. (2016) Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Clin Epigenetics 8:85
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Bunch, Donna O; Mendoza, Carmen E; Aybar, Lydia T et al. (2015) Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis. Ann Rheum Dis 74:1784-6

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