EMBRYONIC RESISTANCE TO TUMOR-NECROSIS-FACTOR-ALPHA MEDIATED CYTOTOXICITY - NOVEL MECHANISM UNDERLYING MATERNAL IMMUNOLOGICAL-TOLERANCE TO THE FETAL ALLOGRAFT

The cytokine tumour necrosis factor-alpha (TNFalpha) has been postulat ed to play an essential role in the cytotoxic activity of cell-mediate d immunity against allogenic or tumour cells invading the host. Severa l tumour cell lines, however, are resistant to TNF mediated cytotoxici ty and respond paradoxically by cellular proliferation and by autocrin e secretion of TNFalpha. In view of the metastatic character of the ma mmalian embryo, the aim of this study was to assess the potential of m urine embryos to secrete TNFalpha in vitro, to express TNF receptors a nd to resist TNFalpha mediated cytotoxicity during their in-vitro deve lopment to the blastocyst stage. The potential of human embryos to sec rete TNFalpha in vitro until the blastocyst stage was also investigate d. From a total of 11 human embryos, which were allowed to proceed to blastocyst formation, seven secreted TNFalpha in the range of 2-117 pg /ml/24 h. A total of 123 C57BL/6J mouse embryos were studied of which 55% secreted TNFalpha in the range of 1.25-3.95 mg/ml/24 h. The presen ce of high levels of exogenous TNFalpha (10-300 IU) was not detrimenta l to the in-vitro development of murine embryos. Using immunohistochem ical techniques, we were not able to detect the presence of type I or II TNF receptors on the surface of murine embryos. Our findings sugges t that human and C57BL/6J murine embryos have the potential to secrete TNFalpha in vitro during the developmental stages leading to blastocy st formation. In both species, the presence of TNFalpha in the culture medium did not cause subsequent necrosis of the conceptus, suggesting that mammalian embryos may be TNFalpha resistant cell lines. The obse rved embryonic resistance to TNFalpha may be explained by the absence of TNF receptors by which the cytotoxic effect is usually mediated. It is suggested that embryonic resistance to physiological concentration s of TNFalpha released by effectors of the host's immune system, could be via a mechanism underlying the maternal immunological tolerance to the fetal allograft.