In immunohistochemical studies investigating the cellular infiltrates in pig xenografts undergoing delayed rejection by newborn and adult primate recipients, we observed extensive infiltration with primate macrophages and natural killer (NK) cells. To extend these studies in vitro, we investigated the functional properties of human NK cell precursors with respect to their potential interactions with pig aortic endothelial cells (PAEC). Using a short-term 51Cr release assay, human peripheral blood mononuclear cells (PBMC) demonstrated spontaneous and interleukin (IL) 2 augmented lytic activity against PAEC which increased with increasing effector to target cell ratio. Treatment of human PBMC with anti-CD2 significantly reduced this NK lytic activity by IL-2-activated PBMC. Finally, we investigated the effects of PAEC treatment with certain macrophage-derived human cytokines on adhesion of IL-2-activated human PBMC. Treatment of PAEC with IL-1 and tumor necrosis factor-α, in a dose-dependent manner, increased adherence of IL-2-activated human PBMC. These results demonstrate that humans contain circulating NK cells capable of lysing PAEC after activation with IL-2, that the mechanism involves interactions between CD2 and its ligand on porcine endothelium, and that these interactions may be influenced by macrophage-derived cytokines produced at the site of xenograft rejection.
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