The Etiological Role of Allogeneic Fetal Rejection in Pre-Eclampsia Haruki Nishizawa 1,3 , Kiyoshi Hasegawa 1 , Machiko Suzuki 1 , Shingo Kamoshida 2 , Takema Kato 3,4 , Kuniaki Saito 5 , Yutaka Tsutsumi 2 , Hiroki Kurahashi 3,4 , Yasuhiro Udagawa 1 1 Department of Obstetrics and Gynecology Fujita Health University School of Medicine, Toyoake, Japan; 2 Department of Pathology, Fujita Health University School of Medicine, Toyoake, Japan; 3 21st Century COE Program, Development Center for Targeted and Minimally Invasive Diagnosis and Treatment, Fujita Health University, Toyoake, Japan; 4 Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan; 5 Department of Informative Clinical Medicine, Gifu University School of Medicine, Gifu, Japan Introduction A fetus can be considered to be a semi-allograft as it comprises 50% self (maternal) and 50% allogeneic (paternal) antigens. From the viewpoint of the immunological response network, pregnancy is also a unique phenomenon as the fetus is not normally rejected by the maternal immune system. In recent years, it has been reported that indoleamine 2,3- dioxygenase (IDO), which is expressed in the placenta, plays a crucial role in the prevention of allogeneic fetal rejection. IDO is the initial and rate- limiting enzyme of the kynurenine pathway that degrades l-tryptophan in macrophages, dendric cells, or trophoblasts. Depletion of l-tryptophan in microenvi- ronment induces G1 arrest and apoptosis of T cells in the maternal circulatory system. As a consequence of this, the suppression of T-cell growth and Keywords Allogeneic fetal rejection, indoleamine 2,3-dioxygenase, placenta, pre-eclampsia Correspondence Haruki Nishizawa, Department of Obstetrics and Gynecology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake, Toyoake, Aichi, 470-1192 Japan. E-mail: nharuki@fujita-hu.ac.jp Submitted December 8, 2006; accepted February 19, 2007. Citation Nishizawa H, Hasegawa K, Suzuki M, Kamoshida S, Kato T, Saito K, Tsutsumi Y, Kurahashi H, Udagawa Y. The etiological role of allogeneic fetal rejection in pre-eclampsia. Am J Reprod Immunol 2007; 58:11–20 doi:10.1111/j.1600-0897.2007.00484.x Problem It has been demonstrated that allogeneic fetal rejection in normal preg- nancy is prevented by placental indoleamine 2,3-dioxygenase (IDO). Further, an immunological etiology has been implicated in pre-eclampsia. Method of study We examined the differences in placental IDO activity between normal and pre-eclamptic pregnancies. Results IDO mRNA expression and enzyme activity levels in the placenta were low in patients with severe pre-eclampsia. The enzyme activity also inversely correlates with the blood pressure of the patients. In the pla- centas from severe pre-eclampsia, IDO immunoreactivity was low, whereas regional T-cell infiltration was observed reciprocally propor- tional to the IDO activity. Conclusion Our findings implicate a potential role for IDO activity and a maternal immunological reaction against an allogeneic fetus in the etiology of pre-eclampsia. ORIGINAL ARTICLE American Journal of Reproductive Immunology 58 (2007) 11–20 ª 2007 The Authors Journal compilation ª 2007 Blackwell Munksgaard 11