PMID- 33544740
OWN - NLM
STAT- MEDLINE
DCOM- 20210708
LR  - 20210708
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 16
IP  - 2
DP  - 2021
TI  - Development of a humanized mouse model to analyze antibodies specific for human 
      leukocyte antigen (HLA).
PG  - e0236614
LID - 10.1371/journal.pone.0236614 [doi]
LID - e0236614
AB  - In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only 
      induce the activation of cellular mediated immune response but also the 
      development of chronic antibody-mediated rejection due to the donor-specific 
      anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the 
      graft endothelium. Significant improvement in long-term survival after 
      transplantation can be expected if antibody-mediated rejection due to the DSA can 
      be overcome. However, the mechanism of producing or controlling the DSA remains 
      to be elucidated. In recent decades, "humanized" mouse models have been widely 
      used for the basic research of human immune systems, but a humanized mouse model 
      to analyze the mechanism of DSA production has not been established yet. Thus, we 
      aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG 
      mouse) administered with human peripheral blood mononuclear cells (PBMCs). 
      Initially, we detected a very low level of human total-IgG and no anti-HLA 
      antibodies (Abs) in these mice. In our next attempt, we mixed PBMCs of various 
      HLA antigenic combinations with or without regulatory T cells and preconditioned 
      them by culturing on feeder cells stably transfected with human CD40 ligand 
      (h-CD40L) alone or with h-CD40L and human B cell activating factor (h-BAFF). They 
      were subsequently co-cultured with the corresponding irradiated stimulator PBMCs, 
      and all cells were administered into naive NSG mice. Although all three humanized 
      models had sufficient human total-IgG and anti-HLA antibody production, 
      allospecific anti-HLA Ab production was prominently suppressed whereas 
      non-specific anti-HLA Abs were sufficiently detected. Therefore, this novel 
      humanized mouse model might be useful for analyzing the mechanism of 
      anti-allogeneic human B cell tolerance induction.
FAU - Yanagawa, Senichiro
AU  - Yanagawa S
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Tahara, Hiroyuki
AU  - Tahara H
AUID- ORCID: 0000-0002-4925-6037
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Shirouzu, Takayuki
AU  - Shirouzu T
AD  - Molecular Diagnostics Division, Wakunaga Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Kawai, Shintaro
AU  - Kawai S
AD  - Molecular Diagnostics Division, Wakunaga Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Tanaka, Yuka
AU  - Tanaka Y
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Ide, Kentaro
AU  - Ide K
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Akimoto, Shuji
AU  - Akimoto S
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Ohdan, Hideki
AU  - Ohdan H
AD  - Department of Gastroenterological and Transplant Surgery, Graduate School of 
      Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210205
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Isoantibodies)
RN  - 147205-72-9 (CD40 Ligand)
SB  - IM
MH  - Animals
MH  - CD40 Ligand/blood/immunology
MH  - Female
MH  - Graft Rejection/*immunology
MH  - Graft Survival/immunology
MH  - HLA Antigens/*analysis/*immunology
MH  - Histocompatibility Antigens Class II
MH  - Humans
MH  - Immunity, Cellular/immunology
MH  - Isoantibodies/blood
MH  - Kidney Transplantation/methods
MH  - Leukocytes, Mononuclear/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Models, Animal
MH  - Organ Transplantation/methods
MH  - Tissue Donors
PMC - PMC7864411
COIS- The authors declare that no competing interests exist. The authors, TS and SK, 
      are affiliated with Wakunaga Pharmaceutical Co., Ltd. (Hiroshima, Japan) and were 
      responsible for measurement of anti-HLA antibodies using WAKFlow developed by 
      this company. This was a scientific collaboration, and there is no commercial 
      relationship between our laboratory in Hiroshima University and Wakunaga 
      Pharmaceutical Co., Ltd. This does not alter the authors' adherence to all the 
      PLOS ONE policies on sharing data and materials.
EDAT- 2021/02/06 06:00
MHDA- 2021/07/09 06:00
PMCR- 2021/02/05
CRDT- 2021/02/05 17:12
PHST- 2020/07/11 00:00 [received]
PHST- 2021/01/21 00:00 [accepted]
PHST- 2021/02/05 17:12 [entrez]
PHST- 2021/02/06 06:00 [pubmed]
PHST- 2021/07/09 06:00 [medline]
PHST- 2021/02/05 00:00 [pmc-release]
AID - PONE-D-20-21268 [pii]
AID - 10.1371/journal.pone.0236614 [doi]
PST - epublish
SO  - PLoS One. 2021 Feb 5;16(2):e0236614. doi: 10.1371/journal.pone.0236614. 
      eCollection 2021.