Abstract:The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C… Show more
“…In an analogous manner, complement plays an important role in disease beyond neutrophil stimulation. C5aR1 modulates development of autoimmunity to MPO, with C5ar1 −/− mice relatively protected from T cell mediated disease, as dendritic cells lacking the C5aR1 are not able to fully activate anti-MPO T cells (22). In contrast, the absence of C3aR did not affect the development of disease in this active model (43).…”
Section: Active Anti-mpo Glomerulonephritis In Micementioning
confidence: 82%
“…C5 deficient mice or mice treated with a neutralizing anti-C5a antibody were protected from glomerular damage after passive transfer of anti-MPO IgG (41). In addition to neutrophil priming, activation of the C5aR on dendritic cells promotes autoimmunity to MPO (22). A C5aR antagonist CCX168 (avacopan) protected mice expressing human C5aR from glomerular injury (21), with subsequent translation into human clinical trials of this compound in the treatment of AAV (42).…”
Section: Transfer Of Anti-mpo Antibodiesmentioning
confidence: 99%
“…This system has also furthered the understanding of the role of complement in neutrophil migration and endothelial injury. C5a was shown to play an important role in MPO-ANCA induced neutrophil retention and activation within the glomerulus (22).…”
Section: Transfer Of Anti-mpo Antibodiesmentioning
confidence: 99%
“…Similar advances have been made in understanding the role of effector T cells (16), complement (17), and the nature of T and B cell epitopes (18)(19)(20) in the pathogenesis of AAV. Furthermore, the judicious use of animal models has allowed pre-clinical investigation of new targeted therapies, exemplified by work on complement in a model involving the passive transfer of anti-MPO antibodies (21,22). Whilst clinical and in vitro research into PR3-AAV is plentiful, no consistent PR3-AAV animal models currently exist, meaning that the in vivo understanding of AAV pathogenesis is based largely on models of anti-MPO disease.…”
“…In an analogous manner, complement plays an important role in disease beyond neutrophil stimulation. C5aR1 modulates development of autoimmunity to MPO, with C5ar1 −/− mice relatively protected from T cell mediated disease, as dendritic cells lacking the C5aR1 are not able to fully activate anti-MPO T cells (22). In contrast, the absence of C3aR did not affect the development of disease in this active model (43).…”
Section: Active Anti-mpo Glomerulonephritis In Micementioning
confidence: 82%
“…C5 deficient mice or mice treated with a neutralizing anti-C5a antibody were protected from glomerular damage after passive transfer of anti-MPO IgG (41). In addition to neutrophil priming, activation of the C5aR on dendritic cells promotes autoimmunity to MPO (22). A C5aR antagonist CCX168 (avacopan) protected mice expressing human C5aR from glomerular injury (21), with subsequent translation into human clinical trials of this compound in the treatment of AAV (42).…”
Section: Transfer Of Anti-mpo Antibodiesmentioning
confidence: 99%
“…This system has also furthered the understanding of the role of complement in neutrophil migration and endothelial injury. C5a was shown to play an important role in MPO-ANCA induced neutrophil retention and activation within the glomerulus (22).…”
Section: Transfer Of Anti-mpo Antibodiesmentioning
confidence: 99%
“…Similar advances have been made in understanding the role of effector T cells (16), complement (17), and the nature of T and B cell epitopes (18)(19)(20) in the pathogenesis of AAV. Furthermore, the judicious use of animal models has allowed pre-clinical investigation of new targeted therapies, exemplified by work on complement in a model involving the passive transfer of anti-MPO antibodies (21,22). Whilst clinical and in vitro research into PR3-AAV is plentiful, no consistent PR3-AAV animal models currently exist, meaning that the in vivo understanding of AAV pathogenesis is based largely on models of anti-MPO disease.…”
“…In vitro neutrophil‐mediated endothelial cell injury induced by ANCA depends on serine protease release . Although neutrophils recruited to the glomerulus in mice with AAV show rapid generation of ROS, mice genetically deficient in NADPH oxidase components (gp91 phox , p47 phox ) demonstrate accelerated ANCA‐mediated crescentic GN, due to loss of ROS‐mediated down‐regulation of IL‐1β . Clearly, neutrophil granule mobilization is a critical component of multiple steps in the pathogenesis of ANCA‐mediated vasculitis.…”
Section: Participation Of Neutrophil Granule Mobilization In Diseasementioning
Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil‐mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.
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