| The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. | |
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MedLine Citation:
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PMID: 21452327 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice. METHODS: Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation. RESULTS: Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum anti-double-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality. CONCLUSION: Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity. |
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Authors:
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Hideharu Sekine; Ting Ting Hsieh Kinser; Fei Qiao; Efrain Martinez; Emily Paulling; Phillip Ruiz; Gary S Gilkeson; Stephen Tomlinson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Arthritis and rheumatism Volume: 63 ISSN: 1529-0131 ISO Abbreviation: Arthritis Rheum. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-31 Completed Date: 2011-05-23 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 0370605 Medline TA: Arthritis Rheum Country: United States |
Other Details:
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Languages: eng Pagination: 1076-85 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 by the American College of Rheumatology. |
Affiliation:
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Medical University of South Carolina, Charleston, SC, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Anti-Idiotypic / blood Antigen-Antibody Complex / blood Autoimmunity / drug effects*, physiology Complement C1q / metabolism Complement C3 / metabolism Complement Inactivating Agents / pharmacology*, therapeutic use* Complement Pathway, Alternative / drug effects*, physiology DNA / immunology Disease Models, Animal Female Immunoglobulin G / blood Kidney / drug effects, pathology Kidney Diseases / drug therapy*, etiology, immunology Lupus Erythematosus, Systemic / complications, drug therapy*, immunology Mice Mice, Inbred MRL lpr Recombinant Fusion Proteins / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HL-082485/HL/NHLBI NIH HHS; R01 HL082485-04/HL/NHLBI NIH HHS; R01 HL086576-04/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Anti-Idiotypic; 0/Antigen-Antibody Complex; 0/CR2-Crry fusion protein, mouse; 0/Complement C3; 0/Complement Inactivating Agents; 0/Immunoglobulin G; 0/Recombinant Fusion Proteins; 80295-33-6/Complement C1q; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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