# Complement in Pathogenesis and Experimental Therapy of ANCA Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $727,668

## Abstract

Although complement is historically not suspected to be implicated in the ‘pauci-immune’ anti-neutrophil
cytoplasmic antibody (ANCA)-associated vasculitis (AAV), recent clinical and experimental evidence has
shown it to play a key role in amplifying the initial inflammation and subsequent orchestration of innate and
adaptive autoimmune organ injury in AAV. Human AAV is a severe systemic autoimmune disease that affects
small vessels in multiple organs, but most prominently the kidney and the respiratory tract. If untreated, AAV is
fatal with an average survival of only 5 months. Current treatment regimens of AAV is limited to non-specific
immunosuppression which carries significant side effects and is not always efficacious in preventing relapse.
Therefore, more effective and less toxic therapeutic approaches are needed. A defining feature of AAV is the
presence in patient’s blood of ANCA with specificity to one of two neutrophil cytoplasmic antigens,
myeloperoxidase (MPO) and proteinase 3. How complement contributes to ANCA-mediated organ injury such
as necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage is not yet fully understood. In this
project, we will use a robust mouse model of MPO ANCA disease that we have recently developed to dissect
the role of complement in NCGN and lung hemorrhage. Additionally, we will use this mouse model to test anti-
complement therapies to provide proof of concept for targeting specific complement proteins in the treatment of
NCGN and lung hemorrhage. Our specific aims are: Aim 1. To test the hypothesis that pathogenesis of both
necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage in our mouse MPO ANCA disease
model requires the interplay between MPO-specific antibodies, alternative pathway of complement, and pre-
existing anti-MPO cellular immunity; Aim 2. To test the role and mechanism of action of complement proteins
and effectors, including properdin, C5aR and membrane attack complex (MAC), in the development of MPO
ANCA-induced NCGN and lung hemorrhage; Aim 3. To test and compare therapeutic efficacy of systemically
blocking properdin, C5, C5a or C5aR in preventing and treating MPO ANCA-induced NCGN and lung
hemorrhage. Our innovative mouse model of MPO ANCA disease fully recapitulates the human disease
phenotype, including development of NCGN and lung hemorrhage. By using this model, we expect to shed
new light on the role of complement in the pathogenesis of AAV, and validate the therapeutic potential of
blocking complement in the treatment of both NCGN and lung hemorrhage, two major disease manifestations
of human AAV.

## Key facts

- **NIH application ID:** 10051265
- **Project number:** 1R01AI148797-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Wenchao Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $727,668
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051265

## Citation

> US National Institutes of Health, RePORTER application 10051265, Complement in Pathogenesis and Experimental Therapy of ANCA Disease (1R01AI148797-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10051265. Licensed CC0.

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