Target Cell Susceptibility to Lysis by Human Natural Killer Cells Is Augmented by ??1,3-Galactosyltransferase and Reduced by ??1,2-Fucosyltransferase

Artrip, John H.; Kwiatkowski, Paweł; Wang, S F; Cortés, Roberto; Schuster, Michael; Ankersmit, Jan; Michler, Robert E.; McKenzie, Ifc; Sandrin, Mauro S.; Itescu, Silviu

doi:10.1097/00007890-199810270-00134

Cited by 20 publications

(34 citation statements)

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“…High frequencies (70-90%) of § -Gal-positive EC were obtained, which enabled us to evaluate the effect of this epitope on human NK cell adhesion and cytotoxicity assays in which primary EC with otherwise identical genetic background were used as controls. In contrast to some investigators [6][7][8]23] and in agreement with others [9], we could not detect any significant effect of § -Gal expression on NK cell adhesion, cytotoxicity or IFN-+ production (Fig. 5, 6).…”

Section: Discussionsupporting

confidence: 85%

“…In some cases, the NK cell susceptibility of PAEC has been compared to the susceptibility of human EC from another anatomical site, e.g. the umbilical vein, which may be irrelevant since it is known that EC phenotypes vary considerably between different vascular beds [7,25]. Second, § -Gal-binding lectins or IgG F(ab') 2 may sterically block § -Gal substituted molecules that are involved in the conjugation of the NK cell to the target even though the § -Gal epitope per se is not involved.…”

Section: Discussionmentioning

confidence: 99%

“…Inverardi et al [6] were the first to suggest that there could be direct cellular recognition of, among other epitopes, the § -Gal determinant; human NK cells were shown to bind COS-7 cells expressing the porcine § 1,3 galactosyltransferase ( § 1,3GalT) and § -Gal but did not bind to non-transfected cells [6]. Artrip et al [7] and Miyagawa et al [8] found that reduced expression of § -Gal on pig EC led to reduced sensitivity to direct NK cell-mediated cytolysis. However, other studies claim that the interaction of human NK cells and porcine endothelium is independent of § -Gal [9].…”

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of α‐Gal on primary human endothelium does not confer susceptibility to NK cell cytotoxicity or increased NK cell adhesion

He¹,

Ehrnfelt²,

Kumagai‐Braesch³

et al. 2004

Eur J Immunol

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The contribution of Gal § 1,3Gal ( § -Gal) to cell-mediated organ xenograft rejection is controversial. We have used recombinant lentiviruses encoding a porcine § 1,3 galactosyltransferase ( § 1,3GalT) to obtain § -Gal-expressing primary human aortic endothelial cells (HAEC) at a frequency of 70-90%. These cells were compared to non-transduced and mock-transduced HAEC with regard to their susceptibility to human NK cell-mediated lysis, ability to stimulate IFN-+ production by NK cells, and support of NK cell adhesion under static and dynamic conditions. Using green fluorescent protein (GFP) as a reporter gene, it was shown that the frequency of green fluorescent HAEC increased until day 5 posttransduction, and at a multiplicity of infection of 2.5, it reached 98%. Lentiviral transduction did not result in activation of HAEC, and transduced HAEC responded as expected to TNF- § and IFN-+ stimulation. No differences were detected between non- § -Gal-and § -Galexpressing HAEC in terms of their susceptibility to NK cell-mediated lysis, ability to stimulate IFN-+ production by NK cells, or ability to support NK cell adhesion under static and dynamic conditions. In conclusion, these data argue against an important role for the § -Gal epitope in the direct interaction between endothelium and NK cells and prove that recombinant lentiviruses are efficient gene carriers for primary human endothelial cells.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of α‐Gal on primary human endothelium does not confer susceptibility to NK cell cytotoxicity or increased NK cell adhesion

He¹,

Ehrnfelt²,

Kumagai‐Braesch³

et al. 2004

Eur J Immunol

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“…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). The molecules involved in triggering Ab-independent NK cell-mediated cytotoxicity to porcine cells are not well defined.…”

mentioning

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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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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“…different expression of histocompatibility complex (MHC) class II proteins. When considering the pig as a potential source of xenogeneic cells, attention should be focused on a role for the Gal-α1,3-Gal epitope expressed on subgroups of porcine cells and secondly on molecules involved in triggering antibody-independent natural killer (NK) cellmediated cytotoxicity (43,47,48). No studies to date have focused on the expression of the Gal-α1,3-Gal epitope on MSC, but some studies suggest that bone marrow progenitor cells express no or little Gal-α1,3-Gal (49) even though conflicting data were reported on porcine embryonic stem cells (50).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of porcine mesenchymal stem cells for therapeutic use in human liver cancer

Groth

Ottinger²,

Kleist³

et al. 2011

Int J Oncol

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Abstract. Mesenchymal stem cell (MSC) transplantation is suggested for therapy of end-stage liver disease, due to e.g. liver cancer and metastasis. Liver transplantation is the only therapeutic option so far but donor organs are short. Also, the availability of allogeneic human MSCs for liver regeneration is limited. Therefore, we evaluated the suitability of porcine bone marrow MSCs from semi-adult pigs and found that morphology, surface expression pattern and multilineage differentiation are similar to those of human MSCs. Porcine MSCs differentiated to a hepatocyte-like phenotype and expressed porcine mRNA of typical liver proteins. However, hepatocyte-like MSCs failed to express the corresponding proteins and did not produce glycogen and urea as primary porcine hepatocytes do. Porcine MSCs were immunotolerated, since they did not activate resting human PBMCs, and were not attacked by human activated PBMCs. However, porcine MSCs led to enhanced proliferation of human pre-activated PBMCs suggesting that immunotoleration of porcine MSCs in the human system has limitations. Together, the potential of porcine MSCs for xenogenous use in human liver therapy is promising but needs further evaluation prior to clinical use.

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Target Cell Susceptibility to Lysis by Human Natural Killer Cells Is Augmented by ??1,3-Galactosyltransferase and Reduced by ??1,2-Fucosyltransferase

Cited by 20 publications

References 0 publications

Aberrant expression of α‐Gal on primary human endothelium does not confer susceptibility to NK cell cytotoxicity or increased NK cell adhesion

Aberrant expression of α‐Gal on primary human endothelium does not confer susceptibility to NK cell cytotoxicity or increased NK cell adhesion

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

Evaluation of porcine mesenchymal stem cells for therapeutic use in human liver cancer

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