Table 2.
Selected models of ANCA associated vasculitis (see Table 1 for animal models of MPO-ANCA associated renal vasculitis).
| Animal | Severity (+ to +++)a | Duration (effector phase) | Contribution to knowledge of pathogenesisb | Limitations | |
|---|---|---|---|---|---|
| EXPERIMENTAL PR3-AAV | |||||
| Passive transfer | |||||
| PR3-specific splenocyte transfer (118) | NOD-SCID mice | ++ to +++ | 20-40 days | Anti-PR3 B and T cells mediate injury; role for regulatory immune response | Poor homology between human and mouse PR3 |
| Passive transfer of human PR3-ANCA to mice reconstituted with human stem cells (119) | Irradiated NOD-SCID-Ill2rγ−/− mice | + | 6 days | In vivo evidence for human PR3-ANCA pathogenicity | Human PR3 present on chimeric neutrophils and monocytes required Challenging immune reconstitution of the mice |
| PULMONARY DISEASE | |||||
| Active anti-MPO autoimmunity with human neutrophil lysosomal extract infusion (84) | Brown Norway rats | ++ to +++ | 14 days | Chronic inflammation and fibrosis seen at 14 days | Granuloma formation unusual in MPO-AAV |
| Active anti-MPO autoimmunity with localized single lung human neutrophil lysosomal extract infusion (83) | Brown Norway rats | ++ | 10 days | Local and systemic effects of neutrophil degranulation | Infusion caused pulmonary damage in the absence of MPO-ANCA |
| Passive transfer of human PR3-ANCA into rats (123) | Wistar rats | ++ to +++ | 24 h | In vivo evidence of pathogenicity of PR3-ANCA | Not strictly autoimmune |
| Perfusion of isolated rat lungs with primed human neutrophils and monoclonal PR3 Ab (124) | CD (SD) rats | ++ | 3 h | Acute lung injury caused by neutrophil degranulation and free oxygen radicals |
Ex vivo model Does not model the process of neutrophil migration to the lungs in vivo |
| OTHER MODELS | |||||
| Passive transfer of LAMP-2 Ab (125) | WKY rats | + to ++ | 5 days | LAMP-2 is an additional target of ANCA | Not all Ab preparations are pathogenic |
| Immunization with FimH (125) | WKY rats | ++ | 39 days | Molecular mimicry may underpin loss of tolerance to LAMP-2 | Antigen processing not taken into account No clear demarcation between induction of immunity and effector responses |
| Spontaneous crescent formation in autoimmune-prone mice (126) | SCG/Kj mice | +++ | Life span 120–135 days | Early onset severe disease | Derived from lupus prone strains Other auto-Ab present Significant immune complex deposition in glomeruli |
| Passive transfer of NET-loaded DC (59) | BALB/c and C57BL/6 mice | ++ to +++ | 3 months | NETs may be involved in development of autoimmunity to MPO and PR3 | Production of other auto-Ab in addition to ANCA Long model, requires multiple DC infusions |
| Passive transfer of PTU-induced abnormal NETs, PTU-induced MPO-ANCA production (127) | WKY rats | + | 30 days | Prolonged MPO exposure via NETs may participate in loss of tolerance | Mild disease |
| Nephrotoxic serum nephritis (128) | C57BL/6 mice | +++ | 7–21 days | Mechanisms of severe nephritis | Mechanistically different effectors No induction of responses to ANCA antigens or transfer of specific cells or Ab |
a
+, mild; ++, moderate; +++ severe.
b
Only initial contribution listed due to space limitations.
Ab, antibody; ANCA, anti-neutrophil cytoplasmic antibodies; CD (SD) Cesarean derived (Sprague-Dawley); DC, dendritic cells; LAMP-2, lysosome-associated membrane protein 2; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; NOD, non-obese diabetic; PR3, proteinase 3; PTU, propylthiouracil; Rag, recombination activating gene; SCG/Kj, spontaneous crescentic glomerulonephritis-forming/Kinjoh; SCID, severe combined immunodeficiency; WKY, Wistar Kyoto.