Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.

Wang, Yi; Hu, Quanteng; Madri, Joseph A.; Rollins, Scott A.; Chodera, A; Matis, Louis A.

doi:10.1073/pnas.93.16.8563

Cited by 309 publications

(173 citation statements)

References 23 publications

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“…Direct support of this hypothesis was first provided by the findings that an inhibitory anti-C5 mAb blocks the development of glomerulonephritis in the (NZB ϫ NZW)F 1 model of SLE (27). Subsequently, direct support for FIGURE 1.…”

Section: Lupus Nephritismentioning

confidence: 73%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

391

350

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The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

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Section: Lupus Nephritismentioning

confidence: 73%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

391

350

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“…Anti-C5 biologic therapy has been extensively investigated in several other animal models of complement-mediated diseases, including collageninduced arthritis and lupus-like autoimmune disease in (NZB/NZW)F 1 mice (19,20). Eculizumab (5G1.1), the humanized anti-C5 mAb, is considered a potential treatment for several chronic inflammatory diseases, including rheumatoid arthritis and nephritis, and phase II trials have been initiated for these indications.…”

Section: Discussionmentioning

confidence: 99%

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Pierangeli¹,

Girardi²,

Vega-Ostertag³

et al. 2005

Arthritis & Rheumatism

331

215

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Objective. Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPLinduced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis.Methods. To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used.Results. Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti-C5 monoclonal antibodies prevented thrombophilia induced by aPL.Conclusion. These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.

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“…The extent of protection was greater in the C3-deficient than C4-deficient animals, suggesting that both classical and alternative complement pathways may be involved in the development of the disease. Further evidence for a role of complement in lupus nephritis was provided by the protection against renal disease provided by anti-C5 Ab treatment of NZB/NZW F 1 mice (13). Based on these studies, C3 in the kidney is postulated to mediate disease by locally activating the inflammatory cascade and by direct complement damage to glomerular tissue through formation of the membrane attack complex.…”

mentioning

confidence: 99%

Complement Component C3 Is Not Required for Full Expression of Immune Complex Glomerulonephritis in MRL/lprMice

Sekine

Reilly

Molano

et al. 2001

The Journal of Immunology

134

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Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3−/−), heterozygous (C3+/−), and C3 wild-type (C3+/+) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3−/− mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3−/− mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

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Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.

Cited by 309 publications

References 23 publications

The Central Role of the Alternative Complement Pathway in Human Disease

The Central Role of the Alternative Complement Pathway in Human Disease

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Complement Component C3 Is Not Required for Full Expression of Immune Complex Glomerulonephritis in MRL/lprMice

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