Document Detail


Porcine UL16-binding protein 1 expressed on the surface of endothelial cells triggers human NK cytotoxicity through NKG2D.
MedLine Citation:
PMID:  16887974     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cellular rejection mechanisms, including NK cells, remain a hurdle for successful pig-to-human xenotransplantation. Human anti-pig NK cytotoxicity depends on the activating receptor NKG2D. Porcine UL16-binding protein 1 (pULBP1) and porcine MHC class I chain-related protein 2 (pMIC2) are homologues of the human NKG2D ligands ULBP 1-4 and MICA and B, respectively. Although transcribed in porcine endothelial cells (pEC), it is not known whether pULBP1 and pMIC2 act as functional ligands for human NKG2D. In this study, surface protein expression of pULBP1 was demonstrated by flow cytometry using a novel pULBP1-specific polyclonal Ab and by cellular ELISA using NKG2D-Fc fusion protein. Reciprocally, pULBP1-Fc bound to primary human NK cells, whereas pMIC2-Fc did not. Transient and stable down-regulation of pULBP1 mRNA in pEC using short-interfering RNA oligonucleotide duplexes and short hairpin RNA, respectively, resulted in a partial inhibition of xenogeneic NK cytotoxicity through NKG2D in (51)Cr release assays. In contrast, down-regulation of pMIC2 mRNA did not inhibit NK cytotoxicity. Human NK cytotoxicity against pEC mediated by freshly isolated or IL-2-activated NK cells through NKG2D was completely blocked using anti-pULBP1 polyclonal Ab. In conclusion, this study suggests that pULBP1 is the predominant, if not only, functional porcine ligand for human NKG2D. Thus, the elimination of pULBP1 on porcine tissues represents an attractive target to protect porcine xenografts from human NK cytotoxicity.
Authors:
Benjamin G Lilienfeld; Carmen Garcia-Borges; Mark D Crew; Jörg D Seebach
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  177     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-04     Completed Date:  2006-09-25     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2146-52     Citation Subset:  AIM; IM    
Affiliation:
Department of Internal Medicine, Laboratory for Transplantation Immunology, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carrier Proteins / biosynthesis,  genetics,  physiology*
Cell Line, Transformed
Cytotoxicity, Immunologic* / genetics
Endothelial Cells / physiology*
Endothelium, Vascular / immunology,  metabolism
Humans
Killer Cells, Natural / immunology*,  metabolism
Ligands
Membrane Proteins / biosynthesis,  physiology*
NK Cell Lectin-Like Receptor Subfamily K
Receptors, Immunologic / physiology*
Receptors, Natural Killer Cell
Swine
Grant Support
ID/Acronym/Agency:
AI 054324/AI/NIAID NIH HHS; AI 49885/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/KLRK1 protein, human; 0/Ligands; 0/Membrane Proteins; 0/NK Cell Lectin-Like Receptor Subfamily K; 0/Receptors, Immunologic; 0/Receptors, Natural Killer Cell

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