The underlying hypothesis of this proposal is that the trophoblast 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-FasLigand system. This hypothesis rests on the fact 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 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 any rejection of the fetus is still unknown. The Fas-FasLigand 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 and induces cell death by binding to its receptor Fas. FasL is expressed in activated T cells and in immune privileged sites such as the testis and eye. The trophoblast constitutes the outer most 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 thereafter 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 immuno privileged properties to the implantation site, the investigators plan to focus their attention mostly on the regulation of FasL expression. To prove the validity of this hypothesis, the investigator proposes a three year plan to: 1) study FasL expression in normal and pathologic human pregnancies; 2) investigate in vitro the regulators of FasL expression; and 3) develop an in vivo animal model to test the hypothesis. If the hypothesis is correct, an imbalance in the Fas-FasL system may cause implantation failure, recurrent pregnancy loss, or preeclampsia. The significance of this proposal is not limited to reproductive problems. It is anticipated that these studies will lead to a better understanding of tumor behavior, actions of chemotherapeutic agents and transplant physiology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-REN (01))
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Yoshinaga, Koji
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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Straszewski-Chavez, Shawn L; Abrahams, Vikki M; Mor, Gil (2005) The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev 26:877-97
Straszewski-Chavez, Shawn L; Abrahams, Vikki M; Funai, Edmund F et al. (2004) X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. Mol Hum Reprod 10:33-41
Abrahams, Vikki M; Straszewski-Chavez, Shawn L; Guller, Seth et al. (2004) First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod 10:55-63
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Mor, Gil; Sapi, Eva; Abrahams, Vikki M et al. (2003) Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes. J Immunol 170:114-22
Chu, Micheline C; Mor, Gil; Lim, Chungyun et al. (2003) Low-grade endometrial stromal sarcoma: hormonal aspects. Gynecol Oncol 90:170-6
Mor, Gil; Abrahams, Vikki M (2003) Potential role of macrophages as immunoregulators of pregnancy. Reprod Biol Endocrinol 1:119
Kamsteeg, Marijke; Rutherford, Thomas; Sapi, Eva et al. (2003) Phenoxodiol--an isoflavone analog--induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22:2611-20
Abrahams, Vikki M; Straszewski, Shawn L; Kamsteeg, Marijke et al. (2003) Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res 63:5573-81

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