Human allogeneic CD2+ lymphocytes activate airway-derived epithelial cells to produce interleukin-6 and interleukin-8. Possible role for the epithelium in chronic allograft rejection

The adhesion of lymphocytes to the epithelium and the release of proinflammatory cytokines are important features observed during acute and chronic allograft rejection. Development of chronic rejection in lung-transplantation patients is preceded by high levels of interleukin (IL)-6 and IL-8 protein in the bronchoalveolar lavage. Therefore, we studied the expression of IL-6 and IL-8 in cocultures of epithelial cells and allogeneic lymphocytes. IL-6 and IL-8 protein levels were determined in supernatants of the airway-derived epithelial cell line A549 and in primary epithelial cells obtained from lung-brushings after coculturing with autologous and allogeneic lymphocytes. Transcriptional mechanisms were detected by transient transfections. Coculture-supernatants of epithelial cells and allogeneic CD2+ lymphocytes show high levels of IL-6 and IL-8 protein due to transcriptional activation of the respective genes in epithelial cells. Highest productions were measured when the epithelial-cell:lymphocyte ratio was 1:10. Highly purified CD4+ and/or CD8+ cells were unable to induce the same response as observed with the total lymphocyte-population. Depletion of CD4+ and/or CD8+ had no effect on the IL-6 and IL-8 production induced by the total CD2+ lymphocyte-population. However, depletion of CD56+ cells diminished the lymphocyte-induced IL-6 and IL-8 production by > 75%. These data show that allogeneic CD2+ lymphocytes are able to activate lung-derived epithelial cells, resulting in the release of proinflammatory cytokines, which have a prominent role in chronic allograft rejection observed in lung-transplantation patients.