Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

Abstract

Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

“…after TBI): macrophages appear as the key players. This sustains the results of Sun et al 42 The thymus and the periphery (i.e. where regulation takes place) are both involved in generating Treg.…”

“…Interestingly, these authors demonstrated that this effect required phagocytosis by host cells. 42 We reported that apoptotic spleen cell infusion with an allogeneic graft prevented anti-BM donor alloimmunization even in mice rejecting their grafts. 35 Treg expansion after apoptotic cell infusion could be beneficial for engraftment as well as to the host (i.e.…”

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

“…Apoptotic splenocytes were obtained using an ultraviolet (UV)-B irradiation method as described, 21 with a minor modification. Briefly, single-cell suspensions of mouse splenocytes were prepared and dead cells or debris were removed using 35% Ficoll.…”

Peripheral Blood Mononuclear Cell Secretome for Tissue Repair

“…Several groups have investigated the effects of injecting apoptotic cells in the transplant setting. The injection of apoptotic splenocytes has been shown to attenuate acute cardiac allograft rejection in rats [77] and mice [91] and ameliorate chronic allograft vasculopathy in mice [80]. In addition, gamma-irradiated splenocytes promote allogeneic bone marrow engraftment [83,84,92].…”