The effect of immunosuppression on bone marrow-derived recipient cells in murine cardiac allografts

Abstract

Cardiac TVD is the major cause of graft failure in patients surviving more than 1 year post-transplantation. TVD is believed to manifest from an interplay between immunological and non-immunological factors, including dyslipidemia and immunosuppressive drugs. Together, these factors trigger events resulting in vascular injury represented by the formation of concentric, lipid-rich plaques. Endothelial cell (EC) injury is an initiating step of the disease process and mounting evidence suggests ECs, as well as smooth muscle cells (SMC), in lesions of allograft vessels, as well as the organ intersitium, derive in part from recipient bone marrow (BM) progenitor cells. We hypothesize that recipient BM-derived cells contribute to the allogeneic and reparative response in the arteries and myocardium of cardiac allografts. This project is designed to characterize the abundance, localization and fate of recipient BM-derived cells in cardiac allografts, as well as the effect of immunosuppression on these recipient cells. 129J murine hearts were transplanted heterotopically into C57BL/6 mice expressing green fluorescent protein (GFP) in either BM cells. A subset of transplanted mice were immunosuppressed with FK506 (6 mg/kg/day). Mice were sacrificed on days 14 and 30. Hearts were examined using confocal and multi-photon microscopy. Recipient BM-derived cells localized to vessel walls and myocardium of transplanted hearts and demonstrated significantly increased seeding to the transplanted heart as compared to native heart controls in immunosuppressed and non-immunosuppressed allograft mice (p 0.05). Non-immunosuppressed and immunosuppressed mice showed 54% and 27% BM-derived recipient cell seeding to the transplanted heart, respectively, as determined on a denominator of total cardiac nuclei. Preliminary data suggests a subset of these cells also stain for vessel wall markers in allograft hearts. Thus, our data suggests recipient BM-derived cells migrate to the transplanted heart early after transplantation. Their functional roles and fate remains to be determined.