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.
Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen
Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized
Early events in cell-mediated recognition of vascularized xenografts: cooperative interactions between selected lymphocyte subsets and natural antibodies
Porcine vascular cell adhesion molecule (VCAM) mediates endothelial cell adhesion to human T cells. Development of blocking antibodies specific for porcine VCAM
Removal of terminal alpha-galactosyl residues from xenogeneic porcine endothelial cells. Decrease in complement-mediated cytotoxicity but persistence of IgG1-mediated antibody-dependent cell-mediated cytotoxicity
Porcine islet cells of Langerhans are destroyed by human complement and not by antibody-dependent cell-mediated mechanisms
In vitro accommodation of immortalized porcine endothelial cells: resistance to complement mediated lysis and down-regulation of VCAM expression induced by low concentrations of polyclonal human IgG antipig antibodies
Human lymphocyte adhesion to xenogeneic porcine endothelial cells: modulation by human TNF-alpha and involvement of VLA-4 and LFA-1
Human NK cell-mediated direct and IgG-dependent cytotoxicity against xenogeneic porcine endothelial cells
T cell independence of macrophage and natural killer cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection
Circulating human mononuclear cells exhibit augmented lysis of pig endothelium after activation with interleukin 2
Accommodation of vascularized xenografts: expression of "protective genes" by donor endothelial cells in a host Th2 cytokine environment
Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts
Human natural killer lymphocytes directly recognize evolutionarily conserved oligosaccharide ligands expressed by xenogeneic tissues
Human NK cell and ADCC reactivity against xenogeneic porcine target cells including fetal porcine islet cells
Role of natural killer cells, macrophages, and accessory molecule interactions in the rejection of pig-to-primate xenografts beyond the hyperacute period
Prolonged discordant xenograft survival and delayed xenograft rejection in a pig-to-baboon orthotopic cardiac xenograft model
Membrane-associated lymphotoxin on natural killer cells activates endothelial cells via an NF-kappaB-dependent pathway
Prevention of initial perfusion failure during xenogeneic ex vivo liver perfusion by selectin inhibition
HLA-G expression protects porcine endothelial cells against natural killer cell-mediated xenogeneic cytotoxicity
Induction of swine major histocompatibility complex class I molecules on porcine endothelium by tumor necrosis factor-alpha reduces lysis by human natural killer cells
High-level porcine endothelial cell expression of alpha(1,2)-fucosyltransferase reduces human monocyte adhesion and activation
Target cell susceptibility to lysis by human natural killer cells is augmented by alpha(1,3)-galactosyltransferase and reduced by alpha(1, 2)-fucosyltransferase.
HLA-G expression on porcine endothelial cells protects partially against direct human NK cytotoxicity but not against ADCC
Alpha-galactosyl-mediated activation of porcine endothelial cells: studies on CD31 and VE-cadherin in adhesion and signaling
Regulation of natural killer cell-mediated swine endothelial cell lysis through genetic remodeling of a glycoantigen
Porcine endothelium supports transendothelial migration of human leukocyte subpopulations: anti-porcine vascular cell adhesion molecule antibodies as species-specific blockers of transendothelial monocyte and natural killer cell migration
Identification, detection, and in vitro characterization of cynomolgus monkey natural killer cells in delayed xenograft rejection of hDAF transgenic porcine renal xenografts
Bcl-2 expression in pig cells suppresses the apoptosis caused by human perforin/granzymes- or FasL/Fas-mediated cytotoxicity
Development of an ex vivo model of pig kidney perfused with human lymphocytes. Analysis of xenogeneic cellular reactions
Alpha-gal-independent dual recognition and activation of xenogeneic endothelial cells and human naïve natural killer cells
Porcine aortic endothelial cells transfected with HLA-G are partially protected from xenogeneic human NK cytotoxicity
Characterization of human killer cell reactivity against porcine target cells: differential modulation by cytokines
Effect of redox modulation on xenogeneic target cells: the combination of nitric oxide and thiol deprivation protects porcine endothelial cells from lysis by IL-2-activated human NK cells
Overexpression of A20 in endothelial cells of vascularized grafts creates a protective barrier against TNF- and FAS-mediated apoptosis
Multiple genetically modified GTKO/hCD46/HLA-E/hβ2-mg porcine hearts are protected from complement activation and natural killer cell infiltration during ex vivo perfusion with human blood
Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype-Effects on immune status and susceptibility to human immune responses.
Prolongation of rat-to-mouse islets xenograft survival by co-transplantation of autologous IL-10 differentiated murine tolerogenic dendritic cells.
Small-Molecule Immunosuppressive Drugs and Therapeutic Immunoglobulins Differentially Inhibit NK Cell Effector Functions in vitro
Genetic engineering of porcine endothelial cell lines for evaluation of human-to-pig xenoreactive immune responses.
Anti-C5 Antibody Tesidolumab Reduces Early Antibody-mediated Rejection and Prolongs Survival in Renal Xenotransplantation.
Selective Identification of α-Galactosyl Epitopes in N-Glycoproteins Using Characteristic Fragment Ions from Higher-Energy Collisional Dissociation.
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