Intrathymic injection of anti-Fas monoclonal antibody prolongs murine non-vascularized cardiac allograft survival

Abstract

Fas is a pro-apoptotic molecule involved in activation-induced cell-death of T lymphocytes, central and peripheral tolerance and immune privilege. We sought to determine the role of Fas in the thymus after organ transplantation. Heterotopic non-vascularized heart transplants from C3H mice were placed in C57Bl/6 recipients. A hamster anti-mouse anti-Fas mAb (JO2) was injected in the thymus of allograft recipients at the time of transplant. Results were compared with intrathymic injections of hamster IgG (HIgG), anti-FasL, as well as surgical thymectomy or intraperitoneal or intravenous injections of JO2 as controls. Intrathymic injection of 5 microg JO2 induced massive thymocyte apoptosis and enhanced allograft survival compared to HIgG (median graft survival 16 days vs 12.5 days, respectively, P=0.01). The effect was receptor and ligand specific. Intraperitoneal or intravenous injections of JO2 did not prolong graft survival. Thymocyte apoptosis was confirmed in vitro, in vivo and in situ. In the thymus, double positive immature CD4+8+ thymocytes were most susceptible to Fas-induced apoptosis. Our data shows that specific modulation of Fas pathways in the thymus at the time of transplant improves modestly but significantly murine heterotopic non-vascularized cardiac allograft survival and is associated with apoptosis of immature CD4+8+ thymocytes.