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Abstract: FR-PO1040

BM-Transplant Mouse Model of MPO-ANCA-GPA

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Alba, Marco A., UNC-Chapel Hill, Chapel Hill, North Carolina, United States
  • Hu, Peiqi, UNC-Chapel Hill, Chapel Hill, North Carolina, United States
  • Xiao, Hong, UNC-Chapel Hill, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Jennette, J. Charles, UNC-Chapel Hill, Chapel Hill, North Carolina, United States
Background

Granulomatosis with polyangiitis is an ANCA-vasculitis characterized by necrotizing granulomatous inflammation and small vessel vasculitis. Pathogenic mechanisms involved in the development of GPA remain poorly understood. Therefore, we sought to develop a reliable murine GPA model.

Methods

MPO-knockout mice (n=8) previously immunized with mouse MPO were exposed to lethal irradiation, followed by transplantation of MPO-expressing bone marrow (1.5x107 BM cells); resulting in circulating anti-MPO antibodies and MPO+ neutrophils. Lipopolysaccharide (LPS, 5µg) was administered by intratracheal instillation 3 weeks after BM transplant; mice were euthanized one week after.

Results

Engraftment of MPO-positive BM in combination of IT LPS resulted in the development of typical pulmonary and kidney ANCA-associated lesions in various phases of evolution, i.e., lung granulomatous lesions and vasculitis in addition to necrotizing crescentic glomerulonephritis (Figure 1).

Conclusion

A reproducible mouse model of MPO-ANCA-GPA is reported. Our results demonstrate that: 1) LPS functions as synergistic pro-inflammatory factor for facilitating anti-MPO induced pulmonary granulomatosis and 2) The effect of long-term exposure to anti-MPO-ANCA resulted in lung and kidney inflammatory lesions of different ages of evolution, closely mimicking human disease.

Funding

  • Other NIH Support