HUMAN T-LYMPHOCYTE PROLIFERATIVE RESPONSE TO RESTING PORCINE ENDOTHELIAL-CELLS RESULTS FROM AN HLA-RESTRICTED, IL-10-SENSITIVE, INDIRECT PRESENTATION PATHWAY BUT ALSO DEPENDS ON ENDOTHELIAL-SPECIFIC, COSTIMULATORY FACTORS

To investigate the mechanisms of cellular rejection in pig-to-human xe notransplantation, the proliferation of different human purified lymph ocyte subpopulations in response to swine leukocyte Ag class II-negati ve porcine aortic endothelial cells (PAEC) was measured in the presenc e or absence of human autologous adherent cells (huAPC), CD8(+) lympho cytes proliferated moderately in the absence of huAPC, and the immune response was slightly increased when huAPC were added, CD56(+) lymphoc ytes failed to proliferate in response to PAEC whether huAPC were pres ent or not. CD4(+) lymphocytes alone did not proliferate in response t o PAEC, but a strong proliferative response was observed in the presen ce of metabolically active huAPC, This response was totally abolished by mAbs directed against HLA class II molecules or by pretreatment of huAPC by human IL-10, Even in the presence of huAPC, CD4+ lymphocytes failed to respond to fixed PAEC or to PAEC-lysates, suggesting that PA EC must be viable to support lymphocyte proliferation. Finally, none o f the nonendothelial porcine adherent cells tested was able to induce human lymphocyte proliferation, despite the fact that they also provid ed a large set of xenogeneic peptides, Our results show that the indir ect presentation pathway of xenoantigens by huAPC to CD4(+) lymphocyte s is crucial in the response to porcine endothelial cells, and that IL -10 could be of therapeutic interest to prevent human lymphocyte activ ation by this pathway. Furthermore, we demonstrated that stimulatory s ignals specifically provided by endothelial cells are also necessary f or this huAPC-restricted proliferative response.