Human TNF can induce nonspecific inflammatory and human immune-mediated microvascular injury of pig skin xenografts in immunodeficient mouse hosts

TNF activates endothelial cells to express cell surface molecules that are necessary to recruit a local infiltrate of leukocytes, Because the actions of this proinflammatory cytokine are not species restricted, we investigate d whether human TNF can up-regulate porcine endothelial adhesion molecules to elicit human T cell infiltration and damage of pig skin xenografts in a chimeric immunodeficient mouse model. We have previously demonstrated the v igorous rejection of human skin allografts and the absence of injury to por cine skin xenografts in human PBMC-SCID/beige mice. Intradermal administrat ion of human TNF at high doses (600 or 2000 ng) caused nonspecific inflamma tory damage of pig skin grafts, whereas low concentrations of TNF (60 or 20 0 ng) resulted in human PBMC-dependent injury of porcine endothelial cells, There was a strong correlation among pig skin xenograft damage, human T ce ll infiltration, and the TNF-induced up-regulation of swine MHC class I and class II molecules, VCAM-1, and, in particular, the de novo expression of porcine E-selectin, The microvascular damage and leukocytic infiltration el icited by TNF were enhanced by porcine IFN-gamma, suggesting that xenograft s may be less prone to cytokine-mediated injury due to the species-restrict ed effects of recipient IFN-gamma, Our results indicate that maintenance of a quiescent endothelium, which does not express E-selectin or other activa tion-dependent adhesion molecules, is important in preventing human anti-po rcine T cell xenoresponses in vivo and that TNF signaling molecules and TNF -responsive gene products are appropriate therapeutic targets to protect ag ainst human T cell-mediated rejection of pig xenografts.