Embryonic resistance to tumour necrosis factor-{alpha} mediated cytotoxicity: novel mechanism underlying maternal immunological tolerance to the fetal allograft

The cytokine tumour necrosis factor- (TNF) has been postulatedto play an essential role in the cytotoxic activity of cell-mediatedimmunity against allogenic or tumour cells invading the host.Several tumour cell lines, however, are resistant to TNF mediatedcytotoxicity and respond paradoxically by cellular proliferationand by autocrine secretion of TNF. In view of the metastaticcharacter of the mammalian embryo, the aim of this study wasto assess the potential of murine embryos to secrete TNF invitro, to express TNF receptors and to resist TNF mediated cytotoxicityduring their in-vitro development to the blastocyst stage. Thepotential of human embryos to secrete TNF in vitro until theblastocyst stage was also investigated. From a total of 11 humanembryos, which were allowed to proceed to blastocyst formation,seven secreted TNF in the range of 2–117 pg/ml/24 h. Atotal of 123 C57BL/6J mouse embryos were studied of which 55%secreted TNF in the range of 1.25–3.95 mg/ml/24 h. Thepresence of high levels of exogenous TNF (10–300 IU) wasnot detrimental to the in-vitro development of murine embryos.Using immunohistochemical techniques, we were not able to detectthe presence of type I or II TNF receptors on the surface ofmurine embryos. Our findings suggest that human and C57BL/6Jmurine embryos have the potential to secrete TNF in vitro duringthe developmental stages leading to blastocyst formation. Inboth species, the presence of TNF in the culture medium didnot cause subsequent necrosis of the conceptus, suggesting thatmammalian embryos may be TNF resistant cell lines. The observedembryonic resistance to TNF may be explained by the absenceof TNF receptors by which the cytotoxic effect is usually mediated.It is suggested that embryonic resistance to physiological concentrationsof TNF released by effectors of the host's immune system, couldbe via a mechanism underlying the maternal immunological toleranceto the fetal allograft.