PMID- 25876079
OWN - NLM
STAT- MEDLINE
DCOM- 20160426
LR  - 20190223
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 4
DP  - 2015
TI  - Immune tolerance induction using fetal directed placental injection in rodent 
      models: a murine model.
PG  - e0123712
LID - 10.1371/journal.pone.0123712 [doi]
LID - e0123712
AB  - OBJECTIVES: Induction of the immune response is a major problem in replacement 
      therapies for inherited protein deficiencies. Tolerance created in utero can 
      facilitate postnatal treatment. In this study, we aimed to induce immune 
      tolerance towards a foreign protein with early gestational cell transplantation 
      into the chorionic villi under ultrasound guidance in the murine model. METHODS: 
      Pregnant C57BL/6 (B6) mice on day 10 of gestation were anesthetized and imaged by 
      high resolution ultrasound. Murine embryos and their placenta were positioned to 
      get a clear view in B-mode with power mode of the labyrinth, which is the 
      equivalent of chorionic villi in the human. Bone marrow cells (BMCs) from 
      B6-Green Fluorescence Protein (B6GFP) transgenic mice were injected into the 
      fetal side of the placenta which includes the labyrinth with glass microcapillary 
      pipettes. Each fetal mouse received 2 x 105 viable GFP-BMCs. After birth, we 
      evaluated the humoral and cell-mediated immune response against GFP. RESULTS: 
      Bone marrow transfer into fetal side of placenta efficiently distributed donor 
      cells to the fetal mice. The survival rate of this procedure was 13.5%(5 out of 
      37). Successful engraftment of the B6-GFP donor skin grafts was observed in all 
      recipient (5 out of 5) mice 6 weeks after birth. Induction of anti-GFP antibodies 
      was completely inhibited. Cytotoxic immune reactivity of thymic cells against 
      cells harboring GFP was suppressed by ELISPOT assay. CONCLUSIONS: In this study, 
      we utilized early gestational placental injection targeting the murine fetus, to 
      transfer donor cells carrying a foreign protein into the fetal circulation. This 
      approach is sufficient to induce both humoral and cell-mediated immune tolerance 
      against the foreign protein.
FAU - Takahashi, Kei
AU  - Takahashi K
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan.
FAU - Endo, Masayuki
AU  - Endo M
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan.
FAU - Miyoshi, Takekazu
AU  - Miyoshi T
AD  - Department of Perinatology and Gynecology, National Cerebral and Cardiovascular 
      Center, Suita, Osaka, Japan.
FAU - Tsuritani, Mitsuhiro
AU  - Tsuritani M
AD  - Department of Perinatology and Gynecology, National Cerebral and Cardiovascular 
      Center, Suita, Osaka, Japan.
FAU - Shimazu, Yukiko
AU  - Shimazu Y
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan.
FAU - Hosoda, Hiroshi
AU  - Hosoda H
AD  - Department of Biochemistry, National Cardiovascular Center Research Institute, 
      Suita, Osaka, Japan.
FAU - Saga, Kotaro
AU  - Saga K
AD  - Department of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Osaka, Japan.
FAU - Tamai, Katsuto
AU  - Tamai K
AD  - Department of Stem Cell Therapy Science, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan.
FAU - Flake, Alan W
AU  - Flake AW
AD  - Center for Fetal Diagnosis and Treatment, The Children's Hospital of 
      Philadelphia, Philadelphia, Pennsylvania, United States of America.
FAU - Yoshimatsu, Jun
AU  - Yoshimatsu J
AD  - Department of Perinatology and Gynecology, National Cerebral and Cardiovascular 
      Center, Suita, Osaka, Japan.
FAU - Kimura, Tadashi
AU  - Kimura T
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan.
LA  - eng
PT  - Journal Article
DEP - 20150413
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 147336-22-9 (Green Fluorescent Proteins)
SB  - IM
MH  - Animals
MH  - *Bone Marrow Transplantation
MH  - Cell Transplantation
MH  - *Chorionic Villi
MH  - Female
MH  - Fetus/*immunology
MH  - Green Fluorescent Proteins/metabolism
MH  - Humans
MH  - Immune Tolerance/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Placenta/*transplantation
MH  - Pregnancy
MH  - *Skin Transplantation
MH  - Tissue Donors
PMC - PMC4395343
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/04/16 06:00
MHDA- 2016/04/27 06:00
PMCR- 2015/04/13
CRDT- 2015/04/16 06:00
PHST- 2014/12/09 00:00 [received]
PHST- 2015/03/06 00:00 [accepted]
PHST- 2015/04/16 06:00 [entrez]
PHST- 2015/04/16 06:00 [pubmed]
PHST- 2016/04/27 06:00 [medline]
PHST- 2015/04/13 00:00 [pmc-release]
AID - PONE-D-14-54182 [pii]
AID - 10.1371/journal.pone.0123712 [doi]
PST - epublish
SO  - PLoS One. 2015 Apr 13;10(4):e0123712. doi: 10.1371/journal.pone.0123712. 
      eCollection 2015.