PMID- 26152192
OWN - NLM
STAT- MEDLINE
DCOM- 20160317
LR  - 20240323
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 6
IP  - 1
DP  - 2015 Jul 8
TI  - Donor antigen-primed regulatory T cells permit liver regeneration and phenotype 
      correction in hemophilia A mouse by allogeneic bone marrow stem cells.
PG  - 129
LID - 10.1186/s13287-015-0119-9 [doi]
LID - 129
AB  - INTRODUCTION: Cell replacement therapy may be considered as an alternate approach 
      to provide therapeutic dose of plasma factor VIII (FVIII) in patients with 
      hemophilia A (HA). However, immune rejection limits the use of allogeneic cells 
      in this mode of therapy. Here, we have examined the role of donor major 
      histocompatibility complex (MHC)-stimulated host CD4(+)CD25(+) regulatory T 
      (Treg) cells in suppressing immune responses against allogeneic uncommitted 
      (Lin(-)) bone marrow cells (BMCs) for correction of bleeding disorder in HA mice. 
      METHODS: Allogeneic donor Lin(-) BMCs were co-transplanted with allo-antigen 
      sensitized Treg cells in HA mice having acetaminophen-induced acute liver injury. 
      Plasma FVIII activity was determined by in vitro functional assay, and correction 
      of bleeding phenotype was assessed on the basis of capillary blood clotting time 
      and tail-clip challenge. The immunosuppression potential of the sensitized Treg 
      cells on CD4(+) T cells was studied both in vitro and in vivo. Suppression of 
      inflammatory reactions in the liver against the homed donor cells by sensitized 
      Treg cells was analysed by histopathological scoring. Allo-specificity of 
      sensitized Treg cells and long-term retention of immunosuppression were examined 
      against a third-party donor and by secondary challenge of allogeneic donor cells, 
      respectively. The engraftment and phenotype change of donor BMCs in the liver and 
      their role in synthesis of FVIII and liver regeneration were also determined. 
      RESULTS: Co-transplantation of allogeneic Lin(-) BMCs with sensitized Treg cells 
      led to systemic immune modulation and suppression of inflammatory reactions in 
      the liver, allowing better engraftment of allogeneic cells in the liver. 
      Allo-antigen priming led to allo-specific immune suppression even after 1 year of 
      transplantation. Donor-derived endothelial cells expressed FVIII in HA mice, 
      leading to the correction of bleeding phenotype. Donor-derived hepatocyte-like 
      cells, which constitute the major fraction of engrafted cells, supported 
      regeneration of the liver after acute injury. CONCLUSIONS: A highly proficient 
      FVIII secreting core system can be created in regenerating liver by transplanting 
      allogeneic Lin(-) BMCs in HA mice where transplantation tolerance against donor 
      antigens can be induced by in vitro allo-antigen primed Treg cells. This strategy 
      can be beneficial in treatment of genetic liver disorders for achieving 
      prophylactic levels of the missing proteins.
FAU - Kochat, Veena
AU  - Kochat V
AD  - Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali 
      Marg, New Delhi, 110067, India. veenak@nii.ac.in.
FAU - Kanjirakkuzhiyil, Sumod
AU  - Kanjirakkuzhiyil S
AD  - Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali 
      Marg, New Delhi, 110067, India. sumod.k@gmail.com.
FAU - Baligar, Prakash
AU  - Baligar P
AD  - Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali 
      Marg, New Delhi, 110067, India. pnbaligar@gmail.com.
FAU - Nagarajan, Perumal
AU  - Nagarajan P
AD  - Experimental Animal Facility, National Institute of Immunology, New Delhi, India. 
      nagarajan@nii.ac.in.
FAU - Mukhopadhyay, Asok
AU  - Mukhopadhyay A
AD  - Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali 
      Marg, New Delhi, 110067, India. ashok@nii.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20150708
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 130068-27-8 (Interleukin-10)
RN  - 9001-27-8 (Factor VIII)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/*cytology
MH  - *Bone Marrow Transplantation
MH  - Chemical and Drug Induced Liver Injury/pathology/therapy
MH  - Coculture Techniques
MH  - Endothelial Cells/cytology/transplantation
MH  - Factor VIII/analysis
MH  - Female
MH  - Hemophilia A/*therapy
MH  - Immune Tolerance
MH  - Immunohistochemistry
MH  - Interleukin-10/analysis
MH  - Kupffer Cells/cytology/transplantation
MH  - Liver/metabolism/pathology
MH  - Liver Regeneration/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Phenotype
MH  - Spleen/cytology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Tissue Donors
MH  - Transplantation, Homologous
PMC - PMC4513683
EDAT- 2015/07/15 06:00
MHDA- 2016/03/18 06:00
PMCR- 2015/07/08
CRDT- 2015/07/09 06:00
PHST- 2015/03/17 00:00 [received]
PHST- 2015/06/25 00:00 [accepted]
PHST- 2015/05/19 00:00 [revised]
PHST- 2015/07/09 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/03/18 06:00 [medline]
PHST- 2015/07/08 00:00 [pmc-release]
AID - 10.1186/s13287-015-0119-9 [pii]
AID - 119 [pii]
AID - 10.1186/s13287-015-0119-9 [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2015 Jul 8;6(1):129. doi: 10.1186/s13287-015-0119-9.