Mouse model for allogeneic immune reaction against fetus recapitulates human pre-eclampsia.
OBJECTIVE
We have previously demonstrated that mRNA expression and enzyme activity levels of placental indoleamine 2,3-dioxygenase (IDO), which degrades L-tryptophan and blocks the proliferation of T cells, are significantly low in patients with severe pre-eclampsia. From this observation, we hypothesized that induction of maternal allogeneic immune reaction by reduced IDO activity is one of the causes of pre-eclampsia.


METHODS
To examine this hypothesis, we administered an IDO inhibitor to pregnant female mice carrying allogeneic concepti. Since administration of an IDO inhibitor to pregnant mice starting at E4.5 is already reported to cause allogeneic fetal rejection, we modified the regimen and started the administration at E6.5 when the fetus and placenta have already been established.


RESULTS
Pregnant mice treated with an IDO inhibitor developed high blood pressure and proteinuria in addition to local circulation impairment in the placenta, which is analogous to the lesions that are characteristic of human pre-eclampsia. In contrast, pregnant mice carrying syngeneic concepti did not manifest such symptoms.


CONCLUSIONS
Our findings reveal a pivotal role for IDO activity in the etiology of pre-eclampsia. These data also lend support to the current hypothesis that pre-eclampsia is one of the possible manifestations of a maternal immunological reaction against an allogeneic fetus.
Nishizawa
Haruki
H
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. nharuki@fujita-hu.ac.jp
Hasegawa
Kiyoshi
K
Suzuki
Machiko
M
Achiwa
Yumiko
Y
Kato
Takema
T
Saito
Kuniaki
K
Kurahashi
Hiroki
H
Udagawa
Yasuhiro
Y
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000503:physiopathology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000187:drug effects*; D011225:Pre-Eclampsia / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D011247:Pregnancy; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D014364:Tryptophan