PMID- 34177940
OWN - NLM
STAT- MEDLINE
DCOM- 20211028
LR  - 20240226
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic 
      Responses in Organ Transplantation.
PG  - 687715
LID - 10.3389/fimmu.2021.687715 [doi]
LID - 687715
AB  - The outcome of organ transplantation is largely dictated by selection of a 
      well-matched donor, which results in less chance of graft rejection. An 
      allogeneic immune response is the main immunological barrier for successful organ 
      transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching 
      diminishes outcomes after solid organ transplantation. The current evaluation of 
      HLA incompatibility does not provide information on the immunogenicity of 
      individual HLA mismatches and impact of non-HLA-related alloantigens, especially 
      in vivo. Here we demonstrate a new method for analysis of alloimmune 
      responsiveness between donor and recipient in vivo by introducing a humanized 
      mouse model. Using molecular, cellular, and genomic analyses, we demonstrated 
      that a recipient's personalized humanized mouse provided the most sensitive 
      assessment of allogeneic responsiveness to potential donors. In our study, HLA 
      typing provided a better recipient-donor match for one donor among two related 
      donors. In contrast, assessment of an allogeneic response by mixed lymphocyte 
      reaction (MLR) was indistinguishable between these donors. We determined that, in 
      the recipient's humanized mouse model, the donor selected by HLA typing induced 
      the strongest allogeneic response with markedly increased allograft rejection 
      markers, including activated cytotoxic Granzyme B-expressing CD8(+) T cells. 
      Moreover, the same donor induced stronger upregulation of genes involved in the 
      allograft rejection pathway as determined by transcriptome analysis of isolated 
      human CD45(+)cells. Thus, the humanized mouse model determined the lowest degree 
      of recipient-donor alloimmune response, allowing for better selection of donor 
      and minimized immunological risk of allograft rejection in organ transplantation. 
      In addition, this approach could be used to evaluate the level of alloresponse in 
      allogeneic cell-based therapies that include cell products derived from 
      pluripotent embryonic stem cells or adult stem cells, both undifferentiated and 
      differentiated, all of which will produce allogeneic immune responses.
CI  - Copyright (c) 2021 Ajith, Mulloy, Musa, Bravo-Egana, Horuzsko, Gani and Horuzsko.
FAU - Ajith, Ashwin
AU  - Ajith A
AD  - Georgia Cancer Center, Department of Medicine, Medical College of Georgia, 
      Augusta University, Augusta, GA, United States.
FAU - Mulloy, Laura L
AU  - Mulloy LL
AD  - Nephrology Division, Department of Medicine, Augusta University, Augusta, GA, 
      United States.
FAU - Musa, Md Abu
AU  - Musa MA
AD  - Georgia Cancer Center, Department of Medicine, Medical College of Georgia, 
      Augusta University, Augusta, GA, United States.
FAU - Bravo-Egana, Valia
AU  - Bravo-Egana V
AD  - Histocompatibility and Immunology Laboratory, Department of Surgery, Medical 
      College of Georgia, Augusta University Medical Center, Augusta, GA, United 
      States.
FAU - Horuzsko, Daniel David
AU  - Horuzsko DD
AD  - Program of Osteopathic Medicine, Philadelphia College of Osteopathic Medicine 
      South Georgia, Moultrie, GA, United States.
FAU - Gani, Imran
AU  - Gani I
AD  - Nephrology Division, Department of Medicine, Augusta University, Augusta, GA, 
      United States.
FAU - Horuzsko, Anatolij
AU  - Horuzsko A
AD  - Georgia Cancer Center, Department of Medicine, Medical College of Georgia, 
      Augusta University, Augusta, GA, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210611
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (HLA Antigens)
RN  - 0 (Isoantibodies)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism
MH  - Cells, Cultured
MH  - Databases, Genetic
MH  - Graft Rejection/immunology/metabolism/*prevention & control
MH  - Graft Survival
MH  - HLA Antigens/genetics/*immunology
MH  - *Histocompatibility
MH  - *Histocompatibility Testing
MH  - Humans
MH  - Isoantibodies/metabolism
MH  - Leukocytes, Mononuclear/immunology/*transplantation
MH  - Lymphocyte Culture Test, Mixed
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - *Organ Transplantation/adverse effects
MH  - Phenotype
MH  - Predictive Value of Tests
MH  - Spleen/*immunology/metabolism
MH  - Transcriptome
MH  - *Transplantation Tolerance
MH  - Transplantation, Homologous
MH  - Mice
PMC - PMC8226140
OTO - NOTNLM
OT  - HLA
OT  - allogeneic
OT  - autologous
OT  - donor selection
OT  - humanized mouse
OT  - immunogenicity
OT  - organ transplantation
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/06/29 06:00
MHDA- 2021/10/29 06:00
PMCR- 2021/01/01
CRDT- 2021/06/28 05:56
PHST- 2021/03/29 00:00 [received]
PHST- 2021/05/28 00:00 [accepted]
PHST- 2021/06/28 05:56 [entrez]
PHST- 2021/06/29 06:00 [pubmed]
PHST- 2021/10/29 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.687715 [doi]
PST - epublish
SO  - Front Immunol. 2021 Jun 11;12:687715. doi: 10.3389/fimmu.2021.687715. eCollection 
      2021.