Induction of Swine Major Histocompatibility Complex Class I Molecules on Porcine Endothelium by Tumor Necrosis Factor-?? Reduces Lysis by Human Natural Killer Cells1

Kwiatkowski, Paweł; Artrip, John H.; Edwards, Niloo M.; Wang, Shu Feng; Michler, Robert E.; Itescu, Silviu

doi:10.1097/00007890-199901270-00005

Cited by 42 publications

(33 citation statements)

References 31 publications

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“…Other studies showed the involvement of the adhesion molecules CD2 and CD49d in NK cell triggering by porcine cells (17), but these may be secondary events to triggering mediated by Gal␣1,3-Gal and CD86. This protective effect would also be in accordance with observations from Kwiatkowski et al (29) that SLA I can play an inhibitory role through some killer Ig-related receptor. It would be interesting to assess these pathways within our system in a future study.…”

Section: Figuresupporting

confidence: 92%

“…IL-2-mediated activation of NK cells increases their cytotoxicity toward porcine cells (27,28). Even if swine leukocyte Ag (SLA) class I may have a protective role through recognition of inhibitory receptors on human NK cells (29), its effect is clearly overridden by activating signals. In the absence of human serum, human NK cells lyse xenogeneic porcine aortic endothelial cells (PAEC) Ͼ2-fold more than allogeneic HUVEC (30,31).…”

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confidence: 99%

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Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Costa

Barber

Fodor

2002

The Journal of Immunology

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Delayed xenograft rejection is a major hurdle that needs to be addressed to prolong graft survival in pig-to-primate xenotransplantation. NK cell activation has been implicated in delayed xenograft rejection. Both Ab-dependent and independent mechanisms are responsible for the high susceptibility of porcine cells to human NK cell-mediated cytotoxicity. Previous reports demonstrated a role of Galα1,3-Gal Ag in triggering the Ab-independent responses. We hypothesize that expression of CD80 and/or CD86 on porcine cells may also play a role in NK cell activation as human NK cells express a variant of CD28. Our initial analysis showed that porcine endothelial cells and fibroblasts express CD86, but not CD80. Genetic engineering of these cells to express hCD152-hCD59, a chimeric molecule designed to block CD86 in cis, was accompanied by a reduction in susceptibility to human NK cell-mediated cytotoxicity. The use of a specific anti-porcine CD86-blocking Ab and the NK92 and YTS cell lines further confirmed the involvement of CD86 in triggering NK cell-mediated lysis of porcine cells. Maximal protection was achieved when hCD152-hCD59 was expressed in H transferase-transgenic cells, which show reduced Galα1,3-Gal expression. In this work, we describe two mechanisms of human NK cell-mediated rejection of porcine cells and demonstrate that genetically modified cells resist Ab-independent NK cell-mediated cytotoxicity.

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Section: Figuresupporting

confidence: 92%

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confidence: 99%

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Costa

Barber

Fodor

2002

The Journal of Immunology

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“…Regarding the subsequent firm adhesion, b 2 -integrins such as CD11a/CD18 and CD11b/CD18 as well as interactions between CD49d and CD106 seem to be involved. Here, a role for CD2 expressed on human NK cells was also demonstrated by Kwiatkowski et al [43], while CD62L interactions appear to be less important than under flow conditions. Finally, the data also indicate that CD162 on human NK cells, CD62E on porcine EC, and CD31 on either cell type have no or only minor influence on the adhesion of human NK cells to porcine EC.…”

Section: Studies On Adhesive Interactions Between Human Nk Cells and supporting

confidence: 77%

Adhesive Interactions between Human NK Cells and Porcine Endothelial Cells

Schneider

Forte

2001

Scand J Immunol

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Human natural killer (NK) cells are able to adhere to xenogeneic porcine endothelial cells (EC) and evidence from in vitro studies as well as animal models suggests a potential role for NK cells in the cellular recognition and damage of porcine xenogeneic tissues. One possible explanation for the observed NK cellmediated xenogeneic cytotoxicity against porcine EC is the molecular incompatibility between porcine major histocompatibility complex (MHC) class I molecules and MHC-specific inhibitory receptors on human NK cells. In this review we attempt to summarize the current knowledge concerning adhesive interactions between human NK cells and porcine EC under special considerations of the cross-species receptor±ligand interactions. Methodological differences in assessing adhesion between various studies are reviewed and comparisons to the syngeneic/allogeneic adhesion mechanisms are made. Finally, the therapeutic potential of blocking antibodies and transgenic HLA expression in preventing NK-cell adhesion and xenogeneic cytotoxicity is discussed.

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“…Our results demonstrate that the expression of HLA-G in either microvascular (2A2) or aortic (PED) pEC provides only partial protection against NK cytotoxicity mediated by polyclonal NK lines, the NK92 cell line, and a panel of NK clones. Since it has been shown that human NK cells may be inhibited, although weakly, by SLA class I molecules (45), differences between HLA-G-transfected pEC and control pEC in the expression of SLA class I may theoretically also explain our results. However, comparable amounts of SLA class I molecules were found on the HLA-G-transfected pEC, and the reversion of the HLA-G-mediated protection observed in blocking experiments using an anti-HLA-class I Ab (data not shown) confirms the ability of HLA-G to inhibit NK cytotoxicity against pEC (25).…”

Section: Discussionmentioning

confidence: 58%

HLA-G Inhibits Rolling Adhesion of Activated Human NK Cells on Porcine Endothelial Cells

Forte

Pazmany

Matter-Reissmann

et al. 2001

The Journal of Immunology

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Human NK cells adhere to and lyse porcine endothelial cells (pEC) and therefore may contribute to the cell-mediated rejection of vascularized pig-to-human xenografts. Since MHC class I molecules inhibit the cytotoxic activity of NK cells, the expression of HLA genes in pEC has been proposed as a potential solution to overcome NK cell-mediated xenogeneic cytotoxicity. HLA-G, a minimally polymorphic HLA class I molecule that can inhibit a wide range of NK cells, is an especially attractive candidate for this purpose. In this study we tested whether the expression of HLA-G on pEC inhibits the molecular mechanisms that lead to adhesion of human NK cells to pEC and subsequent xenogeneic NK cytotoxicity. To this end two immortalized pEC lines (2A2 and PED) were stably transfected with HLA-G1. Rolling adhesion of activated human NK cells to pEC monolayers and xenogeneic cytotoxicity against pEC mediated by polyclonal human NK lines as well as NK clones were inhibited by the expression of HLA-G. The adhesion was partially reversed by masking HLA-G on pEC with anti-HLA mAbs or by masking the HLA-G-specific inhibitory receptor ILT-2 on NK cells with the mAb HP-F1. The inhibition of NK cytotoxicity by HLA-G was only partially mediated by ILT-2, indicating a role for other unknown NK receptors. In conclusion, transgenic expression of HLA-G may be useful to prevent human NK cell responses to porcine xenografts, but is probably not sufficient on its own. Moreover, the blocking of rolling adhesion by HLA-G provides evidence for a novel biological function of HLA molecules.

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Induction of Swine Major Histocompatibility Complex Class I Molecules on Porcine Endothelium by Tumor Necrosis Factor-?? Reduces Lysis by Human Natural Killer Cells1

Cited by 42 publications

References 31 publications

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Adhesive Interactions between Human NK Cells and Porcine Endothelial Cells

HLA-G Inhibits Rolling Adhesion of Activated Human NK Cells on Porcine Endothelial Cells

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