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

Artrip, John H.; Kwiatkowski, Paweł; Michler, Robert E.; Wang, Shu Feng; Tugulea, Sorina; Ankersmit, Hendrik Jan; Chisholm, Larisa; McKenzie, Ian F. C.; Sandrin, Mauro S.; Itescu, Silviu

doi:10.1074/jbc.274.16.10717

Cited by 57 publications

(9 citation statements)

References 48 publications

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“…Differential glycosylation also contributes to direct recognition of pig cells by human NK cells and macrophages (31-33), leading to a response that may be further heightened by cross-species molecular incompatibilities affecting particular cellular interactions (34). Gene sequence analysis suggests that swine leukocyte antigen (SLA) class I, the porcine equivalent of HLA class I, will not transmit an inhibitory signal to receptors on human NK cells (35).…”

Section: The Immune Response To Pig Kidney Xenograftsmentioning

confidence: 99%

Kidney xenotransplantation

Cowan

Cooper

d’Apice

2014

Kidney International

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Xenotransplantation using pigs as donors offers the possibility of eliminating the chronic shortage of donor kidneys, but there are several obstacles to be overcome before this goal can be achieved. Preclinical studies have shown that while porcine renal xenografts are broadly compatible physiologically, they provoke a complex rejection process involving preformed and elicited antibodies, heightened innate immune cell reactivity, dysregulated coagulation, and a strong T cell-mediated adaptive response. Furthermore, the susceptibility of the xenograft to pro-inflammatory and pro-coagulant stimuli is probably increased by cross-species molecular defects in regulatory pathways. To balance these disadvantages, xenotransplantation has at its disposal a unique tool to address particular rejection mechanisms and incompatibilities: genetic modification of the donor. This review focuses on the pathophysiology of porcine renal xenograft rejection, and on the significant genetic, pharmacological and technical progress that has been made to prolong xenograft survival.

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Section: The Immune Response To Pig Kidney Xenograftsmentioning

confidence: 99%

Kidney xenotransplantation

Cowan

Cooper

d’Apice

2014

Kidney International

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“…The contribution of α Gal to NK cell-mediated responses in the absence of natural or induced anti- α Gal Abs remains controversial. Some groups reported that human NK cells directly recognize oligosaccharide ligands expressed by xenogeneic cells [ 87 , 106 , 119 , 120 ]; carbohydrate remodeling of pECs, for instance, increased the susceptibility to human NK-mediated lysis as demonstrated by transfection of α (1,2)-fucosyltransferase in pECs [ 119 ]. Christiansen et al reported interactions between the human NK receptor NKRP1A and α Gal [ 121 ].…”

Section: Strategies To Protect the Porcine Endothelium From Nk Cytmentioning

confidence: 99%

The Role of NK Cells in Pig-to-Human Xenotransplantation

Yung

Schneider

2017

Journal of Immunology Research

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Recruitment of human NK cells to porcine tissues has been demonstrated in pig organs perfused ex vivo with human blood in the early 1990s. Subsequently, the molecular mechanisms leading to adhesion and cytotoxicity in human NK cell-porcine endothelial cell (pEC) interactions have been elucidated in vitro to identify targets for therapeutic interventions. Specific molecular strategies to overcome human anti-pig NK cell responses include (1) blocking of the molecular events leading to recruitment (chemotaxis, adhesion, and transmigration), (2) expression of human MHC class I molecules on pECs that inhibit NK cells, and (3) elimination or blocking of pig ligands for activating human NK receptors. The potential of cell-based strategies including tolerogenic dendritic cells (DC) and regulatory T cells (Treg) and the latest progress using transgenic pigs genetically modified to reduce xenogeneic NK cell responses are discussed. Finally, we present the status of phenotypic and functional characterization of nonhuman primate (NHP) NK cells, essential for studying their role in xenograft rejection using preclinical pig-to-NHP models, and summarize key advances and important perspectives for future research.

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“…Apart from preventing hyperacute rejection, human transferase expressed in porcine cells might also prevent or weaken delayed xenograft rejection. The sensitivity of porcine endothelial cells to lysis caused by the involvement of human natural killer (NK) cells is reduced as a result of human H transferase expression (Artrip et al 1999 ). Expression of human H transferase in the endothelial cells of pigs also limits adhesion and activation of monocytes (Kwiatkowski et al 1999 ).…”

Section: Hyperacute Rejectionmentioning

confidence: 99%

Immune Modulation in Xenotransplantation

Boksa

Zeyland

Słomski

et al. 2014

Arch. Immunol. Ther. Exp.

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The use of animals as donors of tissues and organs for xenotransplantations may help in meeting the increasing demand for organs for human transplantations. Clinical studies indicate that the domestic pig best satisfies the criteria of organ suitability for xenotransplantation. However, the considerable phylogenetic distance between humans and the pig causes tremendous immunological problems after transplantation, thus genetic modifications need to be introduced to the porcine genome, with the aim of reducing xenotransplant immunogenicity. Advances in genetic engineering have facilitated the incorporation of human genes regulating the complement into the porcine genome, knockout of the gene encoding the formation of the Gal antigen (α1,3-galactosyltransferase) or modification of surface proteins in donor cells. The next step is two-fold. Firstly, to inhibit processes of cell-mediated xenograft rejection, involving natural killer cells and macrophages. Secondly, to inhibit rejection caused by the incompatibility of proteins participating in the regulation of the coagulation system, which leads to a disruption of the equilibrium in pro- and anti-coagulant activity. Only a simultaneous incorporation of several gene constructs will make it possible to produce multitransgenic animals whose organs, when transplanted to human recipients, would be resistant to hyperacute and delayed xenograft rejection.

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

Cited by 57 publications

References 48 publications

Kidney xenotransplantation

Kidney xenotransplantation

The Role of NK Cells in Pig-to-Human Xenotransplantation

Immune Modulation in Xenotransplantation

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