Human Natural Killer Lymphocytes Directly Recognize Evolutionarily Conserved Oligosaccharide Ligands Expressed by Xenogeneic Tissues1

Inverardi, Luca; Clissi, Barbara; Stolzer, Amy; Bender, Jeffrey R.; Sandrin, Mauro S.; Pardi, Ruggero

doi:10.1097/00007890-199705150-00021

Cited by 121 publications

(68 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, the blocking experiments suggest that NK cells were only marginally involved in the proliferation of human PBMC in response to PIC. Since adult PIC do not bear the Gala(1,3)Gal epitope [16], our observation is contrary to reports of recognition of pig endothelial cells by human NK cells through the Gala(1,3)Gal epitope [17], even though the islet preparations could be contaminated by Gala(1,3)Gal-positive endothelial cells.…”

Section: Discussioncontrasting

confidence: 99%

Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

et al. 1999

View full text Add to dashboard Cite

Type I diabetes could be treatable by a graft of pig islets [1]. Rejection of this discordant xenograft remains, however, a major problem. Despite advances in the understanding of hyperacute rejection that have made short-term engraftment of porcine tissue a feasible objective, cell-mediated rejection can occur. This cellular rejection could be a serious problem in the case of islets, which are possibly less susceptible to hyperacute rejection [2,3].In vitro human cellular recognition in the discordant human-pig situation has been mainly investigated with stimulator pig lymphocytes or endothelial cells [4±6], i. e. cells which are not intended to be grafted in diabetes. In terms of the disease which islet grafts are intended to combat, it is thus important to characterise human anti-pig islet response since islets have particularities different to lymphocytes, e. g. they do not constitutively express class II molecules Diabetologia (1999) Summary The intensity and mechanisms of cell-mediated rejection of pig islet cells were studied in 49 Type I diabetic and 34 healthy subjects. Human peripheral mononuclear cells proliferated strongly in response to pig islet cells (p < 0.001), though with notable interindividual variations (stimulation index 2 to 215). The variance of stimulation index was higher in diabetic than healthy subjects (p < 0.0001). The response to islet cells was stronger (p < 0.01) than that to pig splenocytes. Proliferation in response to islet cells was strongly decreased (p < 0.01) when CD 4 + T cells were blocked with monoclonal antibodies, whereas the blocking of CD 8 + cells or NK cells gave less pronounced effects. The response to islet cells was decreased (p < 0.01), but not abolished, after antigen-presenting cells were removed. Purified CD 4 + cells alone did not proliferate in response to islet cells but recovered their proliferative ability when mixed with antigen-presenting cells, whereas CD 8 + cells alone proliferated in the presence of interleukin-2 in response to islet cells. Proliferation was blocked (p < 0.01) by anti-DR monoclonal antibodies. During proliferation in response to islet cells, interleukin-10 increased 43-fold (p < 0.01) but interferon-g increased only slightly. No statistical differences were detected between diabetic and control subjects with respect to lymphocyte subsets and the recognition mechanisms or to interferon-g / interleukin-10 production in response to islet cells. These results provide the first detailed information on human cell-mediated xenoreaction to pig islet cells. This situation involves a dominant CD 4 class II-restricted Th2 response, with an indirect recognition pathway, as well as a CD 8 T-cell response resulting from direct recognition. This strong reaction constitutes a serious obstacle which may vary in degree among subjects. [Diabetologia (1999) 42: 330±335]

show abstract

Section: Discussioncontrasting

confidence: 99%

Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

et al. 1999

View full text Add to dashboard Cite

show abstract

“…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: 84%

“…Such an interaction could contribute to later appearing organ xenograft rejection processes, for example acute vascular rejection [5]. 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.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…Increasing evidence suggests that NK cells play a critical role in swine to human xenotransplantation (46,47). Thus, an investigation of the effect of enzymatic remodeling of a glycoantigen, especially ␣-Gal, to NK-mediated direct cytotoxicity was carried out using the PEC from the transgenic pig.…”

Section: Fig 5-continuedmentioning

confidence: 99%

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Miyagawa¹,

Murakami²,

Takahagi³

et al. 2001

Journal of Biological Chemistry

105

View full text Add to dashboard Cite

We have been successful in generating several lines of transgenic mice and pigs that contain the human ␤-Dmannoside ␤-1,4-N-acetylglucosaminyltransferase III (GnT-III) gene. The overexpression of the GnT-III gene in mice and pigs reduced their antigenicity to human natural antibodies, especially the Gal␣1-3Gal␤1-4Glc-NAc-R, as evidenced by immunohistochemical analysis. Endothelial cell studies from the GnT-III transgenic pigs also revealed a significant down-regulation in antigenicity, including Hanganutziu-Deicher antigen, and dramatic reductions in both the complement-and natural killer cell-mediated pig cell lyses. Changes in the enzymatic activities of other glycosyltransferases, such as ␣1,3-galactosyltransferase, GnT-IV, and GnT-V, did not support cross-talk between GnT-III and these enzymes in the transgenic animals. In addition, we demonstrated the effect of GnT-III in down-regulating the xenoantigen of pig heart grafts, using a pig to cynomolgus monkey transplantation model, suggesting that this approach may be useful in clinical xenotransplantation in the future.

show abstract

Human Natural Killer Lymphocytes Directly Recognize Evolutionarily Conserved Oligosaccharide Ligands Expressed by Xenogeneic Tissues1

Abstract: Collectively, our findings suggest that humoral and cellular components of the natural immune response against heterologous species independently evolved recognition patterns directed against overlapping carbohydrate determinants.

Cited by 121 publications

References 32 publications

Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

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

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Contact Info

Product

Resources

About