| Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia-reperfusion injury. | |
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MedLine Citation:
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PMID: 22042224 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Toll-like receptors (TLRs) are important molecules involved in the activation of innate and subsequent development of adaptive immunity. TLRs are ligated by exogenous ligands from pathogens and by endogenous ligands released in inflammatory diseases. Activation of TLR leads to activation of NF-κB and release of proinflammatory cytokines, such as IL-6 and TNF-α. TLRs play an important role in the pathogenesis of renal diseases. Increased expression of TLRs have been associated with ischemic kidney damage, acute kidney injury, end-stage renal failure, acute renal transplant rejection, and delayed allograft function. OPN301 is a mouse anti-human TLR2 antibody that cross-reacts with mouse TLR2. We show that inhibition of TLR2 promotes graft function in an isograft model of renal transplantation. Recipient mice were treated intravenously with OPN301 before reperfusion of the transplanted kidney that had been subjected to 30 min of cold ischemia. After 5 d, the residual native kidney was removed, and renal transplant function was assessed 24 h later by measurement of blood urea nitrogen. Renal function in both saline- and isotype-treated mice was similar, with significant improvement in OPN301-treated mice (isotype-treated vs. OPN301-treated: 33.9±3.2 vs. 19.8±1.9 μM; P<0.01). The histopathological appearance corresponded with renal functional results. In OPN301-treated recipients, renal structure was well preserved, whereas in the saline-treated group, tubular injury was severe, with marked tubular thinning, epithelial shedding, cast formation and necrosis. Inhibition of TLR2 also leads to a decrease in C3d deposition, although it is unclear whether this is due directly to TLR2 inhibition or a decrease in renal inflammation. This study shows that inhibition of TLR2 with a therapeutic agent (OPN301) provides significant protection from ischemia/reperfusion injury in a model of kidney transplantation. |
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Authors:
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Conrad A Farrar; Brian Keogh; William McCormack; Aisling O'Shaughnessy; Andrew Parker; Mary Reilly; Steven H Sacks |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-10-31 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 26 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-01 Completed Date: 2012-04-09 Revised Date: 2012-08-27 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 799-807 Citation Subset: IM |
Affiliation:
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Medical Research Council Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at Guy's, King's College, and St. Thomas' Hospitals, Guy's Hospital, London, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal, Murine-Derived / administration & dosage, pharmacokinetics Complement System Proteins / metabolism Cytokines / biosynthesis Disease Models, Animal Female Humans Kidney / blood supply, injuries, physiopathology Kidney Transplantation / adverse effects*, immunology*, physiology Male Mice Mice, Inbred C57BL Models, Biological Reperfusion Injury / immunology, physiopathology, therapy* Tissue Donors Toll-Like Receptor 2 / antagonists & inhibitors*, immunology, physiology |
| Grant Support | |
ID/Acronym/Agency:
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//Department of Health; //Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal, Murine-Derived; 0/Cytokines; 0/Tlr2 protein, mouse; 0/Toll-Like Receptor 2; 9007-36-7/Complement System Proteins |
| Comments/Corrections | |
Erratum In:
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FASEB J. 2012 Jul;26(7):3096 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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