The underlying hypothesis of this proposal is that the throphoblast induces a transient, specific tolerance to paternal alloantigens by clonal deletion (apoptosis of cytotoxic T cells) and that this process is mediated by the Fas-Fas Ligand system. This hypothesis rest on the facts that during implantation, the maternal immune system is not indifferent to the presence of paternal alloantigens in the fetus. Implantation is known to be followed by a local immune response characterized by the presence of a large population of T cells, many of which express surface markers characteristic of activated T cells and recognize paternal alloantigens. The mechanism preventing an immune rejection of the fetus is still unknown. The Fas-Fas ligand (FasL) system is involved in the turnover of activated mature T cells and/or clonal deletion of autoreactive T cells in the periphery. FasL, a membrane bound protein, delivers an apoptotic signal that induces cell death by binding to its receptor Fas. FasL is expressed in activated T cells and in immune privileged sites, i.e., testis and eye. The trophoblast constitutes the outermost border between maternal and fetal circulation, in contrast to the old concept of a barrier in the mechanical sense, the trophoblast acts as an active and selective barrier, especially to activated T cells. In this setting, activated T cells recognizing placental alloantigens, express Fas, bind to the FasL expressed by the trophoblast, and there undergo apoptosis. This transient tolerance makes the place of implantation an immunologically privileged site. Since the expression of the FasL by the trophoblast is what confers the immunoprivileged properties to the implantation site, we plan to focus our investigations mostly on the regulation of FasL expression. To prove the validity of our hypothesis, we propose a five year plan to: 1) study FasL expression in normal and pathologic human pregnancies (aim 1), 2) investigate in vitro, the regulators of FasL expression (aim 2), and 3) develop an in vivo animal model to test our hypothesis (aim 3). If our hypothesis is correct an imbalance in the Fas-FasL system may cause implantation failure, recurrent pregnancy loss, or preeclampsia (aim 4). The significance of this proposal is not limited to reproductive problems. This study will lead to a better understanding of tumor behavior, actions of chemotherapeutic agents, and transplant physiology.
| Mor, G; Kohen, F; Garcia-Velasco, J et al. (2000) Regulation of fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen. J Steroid Biochem Mol Biol 73:185-94 |
