Multiphoton intravital microscopy visualization of skin graft rejection in real time (126.14)

Abstract

Abstract The current paradigm explaining organ graft rejection postulates that rejection is initiated by graft resident dendritic cells that reach the draining lymph nodes via lymphatics and activate naive alloreactive T cells. These newly activated T cells then migrate into the graft. However up to half the T cells recognizing allogeneic MHC in adult animals are already be of memory phenotype, and thus capable of direct entry into a graft site without prior activation in LNs. This is not the result of previous exposure to allo-Ag, but stems from the fact that the allo-MHC-specific and Ag-specific T cell receptor repertoires overlap each other. These pre-existing allo-reactive T cells represent a major barrier to organ transplantation. To understand the contributions of memory cells to skin graft rejection, we are using intravital multiphoton microscopy to track cellular interactions between memory cells, DCs and lymphatic and vascular endothelium during graft rejection and acceptance. Preliminary studies suggest that DCs from grafts are unable to exit the surgical site, most likely as a result of surgical disruption of lymphatic drainage from the transplanted skin. Further work will investigate trafficking of graft-reactive CD4 effector and Treg cells into the graft site.