Abstract
Despite effective treatment protocols to prevent rejection many renal allografts are lost due to the toxicity of immunosuppressants. Thus, more specific and less toxic immunosuppression is needed. DNAM-1 (CD226) on T cells has been shown to play an important role for allogeneic graft-versus-host responses. DNAM-1 has two ligands: the adhesion molecules CD155 and CD112. Both are expressed on dendritic, epithelial, and endothelial cells. The importance of DNAM-1and its ligands for renal allograft rejection is unknown. Primary cultures of murine renal tubular epithelial cells (rTECs) were prestimulated with IFN-β and IFN-γ to induce high surface expression of MHC. Surface expression of CD155 and CD112 was tested by FACS. Responder T cells were stimulated in vitro with allogeneic fully MHC-mismatched splenocytes. From these stimulation cocultures we measured proliferation (thymidine incorporation), cytokine production (ELISA) and cytotoxicity against IFN-stimulated rTECs from WT or CD155−/− mice (51Cr-release-assay). To test for a role of this pathway in vivo, we performed fully MHC-mismatched skin and kidney grafts from WT and CD155−/− donors. CD155 and CD112 were both highly expressed on rTECs and could be further increased by IFN-stimulation. Also, in acutely rejected murine renal allografts an upregulation of both molecules was detected. However, when CD155 was missing on targets in an allospecific chromium-release-assay, no difference in cytotoxicity was measured compared to WT targets. Also, allospecific T cell proliferation and IFN-γ secretion were not altered, when stimulator cells lacked CD155. When testing for the role of this pathway for allograft rejection in vivo, no difference between skin graft survival of WT and CD155−/−was observed. Renal allografts from CD155−/− donors show similar amounts of infiltrates and interestingly higher incidence of infarcts compared to WT donors. The reason for this is under investigation. In contrast to these results, allospecific T cell proliferation was be reduced with the use of a blocking antibody against DNAM-1. Also allospecific cytotoxicity was reduced, when DNAM-1 was blocked during stimulation. Experiments blocking DNAM1 or CD112 in vivo are ongoing. Thus, DNAM-1 is an important costimulatory receptor for alloreactive T cells. However, the important ligand might be CD112 rather than CD155. Thus, blocking DNAM-1 or CD112 might be a therapeutically interesting option to prevent renal allograft rejection.
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