Abstract
Xenotransplantation of genetically engineered porcine chondrocytes may provide a therapeutic solution for the repair of cartilage defects of various types. However, the mechanisms underlying the humoral and cellular responses that lead to rejection of xenogeneic cartilage are not well understood. In this study, we investigated the interaction between human NK cells and isolated porcine costal chondrocytes (PCC). Our data show that freshly isolated NK cells adhere weakly to PCC. Consequently, PCC were highly resistant to cytolysis mediated by freshly isolated NK cells. However, the presence of human natural Abs in the coculture was often sufficient to trigger cytotoxicity against PCC. Furthermore, IL-2 stimulation of NK cells or activation of PCC with the proinflammatory cytokines TNF-α or IL-1α resulted in increased adhesion, which was paralleled by increased NK cell-mediated lysis of PCC. NK cell adhesion to PCC could be blocked by Abs against human LFA-1 and porcine VCAM-1. NKG2D and NKp44 were involved in triggering cytotoxicity against PCC, which expressed ligands for these activating NK cell receptors. Our data further suggest that NKp30 and NKp46 may contribute to the activation of NK cells by PCC under certain conditions. Finally, comparative studies confirmed that PCC are more resistant than porcine aortic endothelial cells to human NK cell-mediated lysis. Thus, the data demonstrate that human NK cells can kill pig chondrocytes and may therefore contribute to rejection of xenogeneic cartilage. In addition, we identify potential targets for intervention to prevent the NK cell response against pig xenografts.
Highlights
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To study how human NK cells react toward pig chondrocytes, we first assessed the capacity of NK cells to adhere to porcine costal chondrocytes (PCC)
Around 10% of freshly isolated NK cells bound to PCC at 1:1 E:T ratio, and the amount of cells adhered increased with higher E:T ratios
Summary
NKG2D and NKp44 were involved in triggering cytotoxicity against PCC, which expressed ligands for these activating NK cell receptors. Resting pig chondrocytes were highly resistant to lysis mediated by freshly isolated NK cells, the presence of XNA or the activation of either target or effector cells led to efficient cytolysis. To assess whether pig chondrocytes are susceptible to lysis mediated by human NK cells, we determined the cytotoxic activity of freshly isolated NK cells, NK cells activated with hIL-2 overnight or for 3 wk, and NK92 cells against PCC.
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