Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Rinder, Christine S.; Rinder, Henry M.; Smith, Brian R.; Fitch, Jane C.K.; Smith, Michael J.; Tracey, Jayne B.; Matis, Louis A.; Squinto, Stephen P.; Rollins, Scott A.

doi:10.1172/jci118195

Cited by 200 publications

(129 citation statements)

References 71 publications

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“…[13][14][15][16] It was notable that, despite increased C3a and C5a release and abundant surface C3 deposition on DAF/Crry-deficient platelets, we observed no P-selectin or activated ␣IIb␤3 integrin expression on these platelets, suggesting that they did not have an activated phenotype. Neutralization of CD59a and CD59b on DAF/Crrydeficient platelets with blocking mAbs during in vitro complement activation assays moderately increased surface MAC staining (data not shown) but likewise did not induce P-selectin or activated ␣IIb␤3 integrin expression.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have also shown that complement anaphylatoxins C3a and C5a and the membrane attack complex stimulated degranulation and activation of human and animal platelets. [13][14][15][16] To evaluate the physiologic role of membrane complement regulators on platelets, we studied the fate of murine platelets that are deficient in DAF and Crry with the use of an adoptive transfer model. We describe here that platelets deficient in DAF and Crry, but not DAF or Crry alone, were rapidly eliminated from the circulation in an alternative pathway complement-and nonsplenic macrophagedependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Kim

Miwa

Kimura

et al. 2008

Blood

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Complement activation on human platelets is known to cause platelet degranulation and activation. To evaluate how normal platelets escape complement attack in vivo, we studied the fate of murine platelets deficient in 2 membrane complement regulatory proteins using an adoptive transfer model. We show here that deficiency of either decay-accelerating factor (DAF) or complement receptor 1-related gene/protein y (Crry) on murine platelets was inconsequential, whereas DAF and Crry double deficiency led to rapid clearance of platelets from circulation in a complement-and macrophagedependent manner. This finding contrasted with the observation on erythrocytes, where Crry deficiency alone resulted in complement susceptibility. Quantitative flow cytometry revealed that DAF and Crry were expressed at similar levels on platelets, whereas Crry expression was 3 times higher than DAF on erythrocytes. Antibody blocking or gene ablation of the newly identified complement receptor CRIg, but not complement receptor 3 (CR3), rescued DAF/Crry-deficient platelets from complement-dependent elimination. Surprisingly, deficiency of CRIg, CR3, and other known complement receptors failed to prevent Crrydeficient erythrocytes from complementmediated clearance. These results show a critical but redundant role of DAF and Crry in platelet survival and suggest that complement-opsonized platelets and erythrocytes engage different complement receptors on tissue macrophages in

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Kim

Miwa

Kimura

et al. 2008

Blood

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“…The expression of CD55 and CD59 may further modulate complement activation on PMP. CD55 disassembles C3 and C5 convertases (31), whereas CD59 prevents the formation of the terminal complement complex (C5b-9), which can contribute to platelet and endothelial cell activation at sublytic concentrations [44,45].…”

Section: Discussionmentioning

confidence: 99%

Expression of complement components and inhibitors on platelet microparticles

2008

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Platelet microparticles (PMP) are released from activated platelets and play an important role in hemostasis, thrombosis and inflammation. Since platelets were recently found to demonstrate an intrinsic capacity for activating both classical and alternative pathways of the complement system, the present study extended these observations to PMP. PMP were generated by treating platelets with 10 µM A23187 (37°C, 5 min). PMP were identified by flow cytometry, based on size, Annexin V binding, and expression of P-selectin and GPIIb (CD41). PMP expressed gC1qR/p33, a multifunctional cellular protein that was recently described to activate the classical complement cascade. PMP also expressed the classical pathway and contact system regulator, CI inhibitor (C1-INH), as well as CD55 and CD59. Despite C1-INH expression, PMP supported classical pathway C4 activation in the presence of purified C1 and C4. Moreover, statistically significant deposition of C3b and C5b-9 was detected on PMP exposed to plasma, concurrently with expression of CD55 and CD59. These data provide the first evidence for the ability of PMP to support in situ complement activation. Complement activation contributes to a variety of vascular and inflammatory disease states including atherosclerosis and ischemia/reperfusion injury.

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“…The plates were incubated for 30 min at room temperature. Erythrocyte preparation and hemolytic assays were then performed as described (18).…”

Section: Methodsmentioning

confidence: 99%

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

Wang

Rollins

Madri

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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327

227

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Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors CSa and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.

show abstract

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Cited by 200 publications

References 71 publications

Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Expression of complement components and inhibitors on platelet microparticles

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

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