Development of a novel method for Induction of Fetal Immunological Tolerance using Maternal microchymerism

• Project/Area Number: 18K09228
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Osaka University
• Principal Investigator: Endo Masayuki 大阪大学, 医学系研究科, 教授 (30644794)
• Co-Investigator(Kenkyū-buntansha): 玉井 克人 大阪大学, 医学系研究科, 寄附講座教授 (20236730)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 胎児 / 免疫寛容 / マイクロキメリズム / 間葉系幹細胞 / 細胞移植 / 胎児治療

Outline of Final Research Achievements

The phenomenon of cell migration from the mother to the fetus during pregnancy is called maternal-microchimerism. This mechanism has been shown to cause a certain percentage of children to develop an immunological tolerance to cells of maternal origin. In this case, the child does not reject maternally derived cell transplants or proteins specific to the mother. In this study, we sought to increase the efficiency of induction of immune tolerance against maternal derived protein. By administering the mesenchymal stem cell mobilization factor, HMGB1, to pregnant mice, we hoped that more mesenchymal stem cells would be transferred from the maternal blood to the fetus. As a result, we were able to increase the efficiency of immune tolerance induction by about 4-fold.

Academic Significance and Societal Importance of the Research Achievements

母親由来細胞やタンパク質に対して免疫寛容があると、その子供は母親由来の細胞移植や、母親に特異的なタンパク質に対して拒絶反応を起こしません。
もし、子供に特殊な疾患があって、細胞移植治療や臓器移植、あるいはタンパク質補充療法などの治療が必要な場合、通常であれば免疫抑制剤を使用したり、治療前に化学療法や放射線療法などで骨髄抑制をする必要があります。しかし、免疫寛容が誘導されていれば、そのような処置も必要なく治療することが可能になります。

Research Products

• [Journal Article] Controlled induction of immune tolerance by mesenchymal stem cells transferred by maternal microchimerism. (2020)
  • Author(s): Iwai S, Okada A, Sasano K, Endo M, Yamazaki S, Wang X, Shimbo T, Tomimatsu T, Kimura T, Tamai K
  • Journal Title: Biochem Biophys Res Commun Volume: 539 Pages: 83-88
  • DOI: 10.1016/j.bbrc.2020.12.032
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of leucine-rich alpha-2 glycoprotein as a biomarker of fetal infection (2020)
  • Author(s): Kajimoto Etsuko、Endo Masayuki、Fujimoto Minoru、Matsuzaki Shinya、Fujii Makoto、Yagi Kazunobu、Kakigano Aiko、Mimura Kazuya、Tomimatsu Takuji、Serada Satoshi、Takeuchi Makoto、Yoshino Kiyoshi、Ueda Yutaka、Kimura Tadashi、Naka Tetsuji
  • Journal Title: PLOS ONE Volume: 15 Issue: 11 Pages: 0242076-0242076
  • DOI: 10.1371/journal.pone.0242076
  • Peer Reviewed / Open Access
• [Journal Article] Sonographic findings after induced medical abortion at 12?21?weeks of gestation: Retrospective cohort study (2020)
  • Author(s): Mimura Kazuya、Endo Masayuki、Kakigano Aiko、Matsuzaki Shinya、Kawanishi Yoko、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Contraception Volume: 102 Issue: 2 Pages: 87-90
  • DOI: 10.1016/j.contraception.2020.04.014
  • Peer Reviewed
• [Journal Article] Feasibility and outcomes of fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: A Japanese experience (2020)
  • Author(s): Wada Seiji、Ozawa Katsusuke、Sugibayashi Rika、Suyama Fumio、Amari Shoichiro、Ito Yushi、Kanamori Yutaka、Okuyama Hiroomi、Usui Noriaki、Sasahara Jun、Kotani Tomomi、Hayakawa Masahiro、Kato Kiyoko、Taguchi Tomoaki、Endo Masayuki、Sago Haruhiko
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 12 Pages: 2598-2604
  • DOI: 10.1111/jog.14504
  • Peer Reviewed
• [Journal Article] Efficacy of Prophylactic Antibiotics in Bakri Intrauterine Balloon Placement: A Single-Center Retrospective Analysis and Literature Review (2020)
  • Author(s): Nagase Y, Matsuzaki S, Kawanishi Y, Nakagawa S, Kakigano A, Takiuchi T, Mimura K, Tomimatsu T, Endo M, Kimura T.
  • Journal Title: American Journal of Perinatology Reports Volume: 10(1) Issue: 01 Pages: e106-e112
  • DOI: 10.1055/s-0040-1708487
  • Peer Reviewed / Open Access
• [Journal Article] Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library. (2020)
  • Author(s): Yagi K, Mimura K, Tomimatsu T, Matsuyama T, Kawanishi Y, Kakigano A, Nakamura H, Endo M, Kimura T.
  • Journal Title: PLoS One. Volume: 15 Issue: 12 Pages: 0244684-0244684
  • DOI: 10.1371/journal.pone.0244684
  • Peer Reviewed / Open Access
• [Journal Article] Obstetric Outcomes of Pregnancy After Uterine Artery Embolization</p> (2020)
  • Author(s): Jitsumori Mariko、Matsuzaki Shinya、Endo Masayuki、Hara Takeya、Tomimatsu Takuji、Matsuzaki Satoko、Miyake Tatsuya、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Kobayashi Eiji、Ueda Yutaka、Kimura Tadashi
  • Journal Title: International Journal of Women's Health Volume: Volume 12 Pages: 151-158
  • DOI: 10.2147/ijwh.s236443
  • Peer Reviewed / Open Access
• [Journal Article] Persistent funic presentation due to velamentous cord insertion adjacent to the internal os but not vasa previa (2020)
  • Author(s): Mimura Kazuya、Endo Masayuki、Matsuzaki Shinya、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Taiwanese Journal of Obstetrics and Gynecology Volume: 59 Issue: 1 Pages: 167-168
  • DOI: 10.1016/j.tjog.2019.10.001
  • Peer Reviewed / Open Access
• [Journal Article] Successful management of fetal hemolytic disease due to strong anti-Rh17 with plasma exchange and intrauterine transfusion in a woman with the D--phenotype. (2020)
  • Author(s): Mimura K, Endo M, Takahashi A, Doi Y, Sakuragi M, Kiyokawa T, Taniguchi H, Kitabatake Y, Handa M, Tomimatsu T, Tomiyama Y, Isaka Y, Kimura T.
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 1 Pages: 149-154
  • DOI: 10.1007/s12185-019-02735-6
  • Peer Reviewed / Open Access
• [Journal Article] Horizontal Cervix as a Novel Sign for Predicting Adhesions on the Posterior Extrauterine Wall in Cases of Placenta Previa (2019)
  • Author(s): Matsuzaki Shinya、Okada Aiko、Endo Masayuki、Nagase Yoshikazu、Nakagawa Satoshi、Hiramatsu Kosuke、Kakigano Aiko、Mimura Kazuya、Takiuchi Tsuyoshi、Tomimatsu Takuji、Ueda Yutaka、Ogita Kazuhide、Kimura Tadashi
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 12 Pages: 2141-2141
  • DOI: 10.3390/jcm8122141
  • Peer Reviewed / Open Access
• [Journal Article] Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors (2019)
  • Author(s): Tomimatsu Takuji、Mimura Kazuya、Matsuzaki Shinya、Endo Masayuki、Kumasawa Keiichi、Kimura Tadashi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 17 Pages: 4246-4246
  • DOI: 10.3390/ijms20174246
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Characteristics of Jra Alloimmunization in Pregnancy: A Case Series (2019)
  • Author(s): Kanagawa Takeshi、Fujikawa Eri、Mimura Kazuya、Endo Masayuki、Sasahara Jun、Kimura Tadashi、Mitsuda Nobuaki、Ishii Keisuke
  • Journal Title: Fetal Diagnosis and Therapy Volume: 46 Issue: 6 Pages: 433-439
  • DOI: 10.1159/000501517
  • Peer Reviewed
• [Journal Article] Transcriptionally distinct mesenchymal stem/stromal cells circulate in fetus (2019)
  • Author(s): Shimbo, T., Endo, M., Iwai; S., Kitayama, T., Ouchi, Y., Yamamoto, R., Takaki, E., Yamazaki, S., Nishida, M., Wang, X., Kikuchi, Y., Tomimatsu, T., Kaneda, Y., Kimura, T. Tamai, K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: pii: S0006-291X(19) Issue: 2 Pages: 30410-3
  • DOI: 10.1016/j.bbrc.2019.03.033
  • Peer Reviewed / Open Access
• [Journal Article] New dedicated blunt straight needles and sutures for uterine compression sutures: a retrospective study and literature review (2019)
  • Author(s): Matsuzaki Shinya、Endo Masayuki、Tomimatsu Takuji、Nakagawa Satoshi、Matsuzaki Satoko、Miyake Tatsuya、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Ueda Yutaka、Kimura Tadashi
  • Journal Title: BMC Surgery Volume: 19 Issue: 1 Pages: 33-33
  • DOI: 10.1186/s12893-019-0495-7
  • Peer Reviewed / Open Access
• [Journal Article] Cervical cancer screening rate differs by HPV vaccination status: An interim analysis (2019)
  • Author(s): Taniguchi Mariko、Ueda Yutaka、Yagi Asami、Ikeda Sayaka、Endo Masayuki、Tomimatsu Takuji、Nakayama Tomio、Sekine Masayuki、Enomoto Takayuki、Kimura Tadashi
  • Journal Title: Vaccine Volume: 37 Issue: 32 Pages: 4424-4426
  • DOI: 10.1016/j.vaccine.2019.06.064
  • Peer Reviewed
• [Journal Article] Nationwide survey of fetal myelomeningocele in Japan: Background for fetal surgery (2019)
  • Author(s): Takahashi Yuka Otera、Wada Seiji、Miya Michiko、Akaishi Rina、Sugibayashi Rika、Ozawa Katsusuke、Endo Masayuki、Sago Haruhiko
  • Journal Title: Pediatrics International Volume: 61 Issue: 7 Pages: 715-719
  • DOI: 10.1111/ped.13889
  • Peer Reviewed
• [Journal Article] Gross image of vasa previa restored in the postpartum period (2018)
  • Author(s): Matsuzaki Shinya、Kakigano Aiko、Mimura Kazuya、Nagase Yoshikazu、Endo Masayuki、Kimura Tadashi
  • Journal Title: Clinical Case Reports Volume: 7 Issue: 2 Pages: 383-384
  • DOI: 10.1002/ccr3.1979
  • Peer Reviewed / Open Access
• [Journal Article] An evident asymmetrical uterus during cesarean delivery (2018)
  • Author(s): Kakigano Aiko、Matsuzaki Shinya、Jitsumori Mariko、Mimura Kazuya、Endo Masayuki、Kimura Tadashi
  • Journal Title: Clinical Case Reports Volume: 6 Issue: 11 Pages: 2281-2282
  • DOI: 10.1002/ccr3.1802
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal findings of serpentine-like syndrome with congenital intrathoracic stomach: differential diagnosis from congenital diaphragmatic hernia (2018)
  • Author(s): Mimura Kazuya、Endo Masayuki、Matsuoka Keiko、Tomimatsu Takuji、Tazuke Yuko、Okuyama Hiroomi、Takeuchi Makoto、Kimura Tadashi
  • Journal Title: Journal of Medical Ultrasonics Volume: 46 Issue: 2 Pages: 263-266
  • DOI: 10.1007/s10396-018-0896-8
  • Peer Reviewed / Open Access
• [Journal Article] Obstetric outcomes and acceptance of alternative therapies to blood transfusion by Jehovah’s Witnesses in Japan: a single-center study (2018)
  • Author(s): Tanaka Mie、Matsuzaki Shinya、Endo Masayuki、Kakigano Aiko、Mimura Kazuya、Takiuchi Tsuyoshi、Miyake Tatsuya、Tomimatsu Takuji、Ueda Yutaka、Kimura Tadashi
  • Journal Title: International Journal of Hematology Volume: 108 Issue: 4 Pages: 432-437
  • DOI: 10.1007/s12185-018-2490-7
  • Peer Reviewed / Open Access
• [Journal Article] Arginase controls soluble vascular endothelial growth factor receptor 1 (sFlt1) to maintain pregnancy homeostasis (2018)
  • Author(s): Tanaka Hiroko、Kumasawa Keiichi、Kakigano Aiko、Mimura Kazuya、Endo Masayuki、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 499 Issue: 2 Pages: 150-155
  • DOI: 10.1016/j.bbrc.2018.03.086
  • Peer Reviewed / Open Access
• [Journal Article] Obstetric outcome in patients with a unicornuate uterus after laparoscopic resection of a rudimentary horn (2018)
  • Author(s): Sawada, M. Kakigano, A. Matsuzaki, S. Takiuchi, T. Mimura, K. Kumasawa, K. Endo, M. Ueda, Y. Yoshino, K. Kimura, T.
  • Journal Title: J Obstet Gynaecol Res Volume: - Issue: 6 Pages: 1080-1086
  • DOI: 10.1111/jog.13622
  • Peer Reviewed / Open Access
• [Journal Article] Conservative management of placenta percreta (2018)
  • Author(s): Matsuzaki Shinya、Yoshino Kiyoshi、Endo Masayuki、Kakigano Aiko、Takiuchi Tsuyoshi、Kimura Tadashi
  • Journal Title: International Journal of Gynecology & Obstetrics Volume: 140 Issue: 3 Pages: 299-306
  • DOI: 10.1002/ijgo.12411
  • Peer Reviewed / Open Access
• [Journal Article] 妊娠初期における妊婦のリスク評価と具体的対策 (2018)
  • Author(s): 遠藤誠之
  • Journal Title: 日本医事新報 Volume: 4913 Pages: 28-31
  • Peer Reviewed
• [Journal Article] 胎児治療：Fetus as a patient (2018)
  • Author(s): 遠藤誠之
  • Journal Title: 産婦人科の進歩 Volume: 70 Pages: 323-327
  • NAID: 130007492060
  • Peer Reviewed
• [Presentation] Fetal Shunting with Harrison’s Pigtail (2019)
  • Author(s): Endo M.
  • Organizer: Pertemuan Ilmiah XX Fetomaternal Bandung 2019.
  • Int'l Joint Research
• [Presentation] LUTO and Vesicoamniotic shunting. (2019)
  • Author(s): Endo M.
  • Organizer: Pertemuan Ilmiah XX Fetomaternal Bandung 2019.
  • Int'l Joint Research
• [Presentation] In-utero shunting for PUV (2019)
  • Author(s): Endo M.
  • Organizer: 3rd Thailand Ian Donald Advanced Course of Ultrasound in Obstetrics and Gynecology & 5th Asia-Pacific Conference of Fetal Therapy 2019
  • Int'l Joint Research / Invited
• [Presentation] In utero gene therapy for cleft palate (2019)
  • Author(s): 遠藤誠之
  • Organizer: 第59回日本先天異常学会ならびに13th World Congress of the International Cleft Lip and Palate Foundation(CLEFT2019)
  • Int'l Joint Research
• [Presentation] 本邦における脊髄髄膜瘤胎児手術に向けての取り組み１ (2019)
  • Author(s): 遠藤誠之、奥山宏臣、渡邊美穂、香川尚己、味村和哉、木村正、和田誠司、左合治彦
  • Organizer: 第17回日本胎児治療学会
• [Presentation] 総論：胎児治療の過去、現在、そして未来 (2019)
  • Author(s): 遠藤誠之
  • Organizer: 第17回日本胎児治療学会
  • Invited
• [Presentation] 脊髄髄膜瘤胎内手術の現状と展望 (2018)
  • Author(s): 遠藤誠之
  • Organizer: 第38回日本脳神経外科コングレス総会
• [Presentation] Mesenchymal stem cell can induce offsprings' immune tolerance against non-inherited antigens in murine maternal-to-fetal microchimeric model (2018)
  • Author(s): Endo M.
  • Organizer: Inrenational Fetal Medicine and Surgery Society
  • Int'l Joint Research
• [Presentation] Fetoscopic ballon removal or Exit removal? Endo M, (2018)
  • Author(s): Endo M.
  • Organizer: 4th Asia Pacific Conference on Fetal Therapy
  • Int'l Joint Research
• [Presentation] Osteogenesis imperfect (2018)
  • Author(s): Endo M.
  • Organizer: 4th Asia Pacific Conference on Fetal Therapy
  • Int'l Joint Research
• [Presentation] Shunting for LUTO(hakko Shunt) (2018)
  • Author(s): Endo M.
  • Organizer: 4th Asia Pacific Conference on Fetal Therapy
  • Int'l Joint Research
• [Presentation] Fetal Surgery (2018)
  • Author(s): Endo M.
  • Organizer: First Maternity Hospital 90th Anniversary Event and International Seminar
  • Invited
• [Presentation] Mesenchymal stem cell can induce offspring’s immune tolerance against non!inherited antigens in murine Maternal!to!Fetal microchimeric model (2018)
  • Author(s): Okada A, Endo M, Sasano K, Kawanishi Y, Owa T, Kajimoto E, Tanaka H, Kakigano A, Mimura K, Tomimatsu T, Tamai K, Kimura T.
  • Organizer: 第70回日本産科婦人科学会
• [Presentation] <生涯研修プログラム16 胎児治療> (2018)
  • Author(s): 遠藤誠之.
  • Organizer: 第70回日本産科婦人科学会
• [Presentation] 出生前診断された先天性横隔膜ヘルニア症例における出生時週数と児の予後に関する検討 (2018)
  • Author(s): 川西陽子, 遠藤誠之, 甘利昭一郎, 臼井規朗, 内田恵一, 漆原直人, 岡和田学, 金森 豊, 田口智章, 照井慶太, 豊島勝沼, 早川昌弘, 古川泰三, 横井暁子, 奥山宏臣.
  • Organizer: 第54回日本周産期・新生児医学会
• [Presentation] 脊髄髄膜瘤胎内手術： 産科医の立場から (2018)
  • Author(s): 遠藤誠之.
  • Organizer: 日本脳神経外科学会第77回学術総会
• [Book] 胎児発育不全 (2018)
  • Author(s): 金山 尚裕、池田 智明、味村和哉、遠藤誠之，他
  • Total Pages: 196
  • Publisher: 中外医学社
  • ISBN: 9784498060906