Induction of swine major histocompatibility complex class I molecules on porcine endothelium by tumor necrosis factor-alpha reduces lysis by human natural killer cells

Background. Natural killer (NK) cells have been implicated in a process of delayed xenograft rejection occurring in pig-to-primate organ transplants. As tumor necrosis factor-alpha (TNF-alpha) induces expression of both adhes ion receptors and major histocompatibility complex class I molecules on por cine endothelium, we investigated the effects of TNF-alpha on human NK cell adherence to and cytotoxicity of porcine aortic endothelial cell (PAEC) mo nolayers. Methods. Adherence of human NK cells was measured after PAEC treatment with increasing concentrations of TNF-alpha. Monoclonal antibodies (mAbs) again st adhesion molecules on NK, cells and PAEC were used in inhibition studies . Resting or TNF-alpha-treated PAEC were used as targets for NK lysis. Incr easing titers of anti-swine leukocyte antigen (SLA) class I antibodies or p ooled human immune globulin (IVIg) were used to reverse the effects of TNF- alpha on NK lysis. Results. NK cell adhesion to TNF-alpha-treated PAEC increased in a dose-dep endent manner by a maximum of 44%, and was inhibited by mAbs against CD49d, CD11a, CD11b, CD18, and CD2, as well as porcine vascular cell adhesion mol ecules, In contrast, TNF-alpha treatment of PAEC reduced human NK lysis in a dose-dependent manner, Preincubation of TNF-alpha-treated PAEC with incre asing concentrations of anti-SLA class I mAb increased NK lysis in a titer- dependent manner, and reversed the protective effect on human Mt lysis by 7 7%, Treatment with IVIg, containing antibodies against an alpha-helical reg ion of HLA class I molecules, had a similar effect. Conclusions. These results imply that SLA class I molecules can bind to inh ibitory receptors on human NK cells, and that these interactions can be aug mented by increasing the level of SLA class I molecule expression on porcin e endothelium. Strategies that can increase porcine endothelial cell expres sion of either swine or human major histocompatibility complex class I mole cules may reduce human NK activity against porcine xenografts.