Details:

Alternative Title:
Am J Transplant
Publisher's site:
http://dx.doi.org/10.1111/ajt.16882
Personal Author:
Tran, Danh T. ; Tu, Zhenxiao ; Alawieh, Ali ; Mulligan, Jennifer ; Esckilsen, Scott ; ... More +
Tran, Danh T. ; Tu, Zhenxiao ; Alawieh, Ali ; Mulligan, Jennifer ; Esckilsen, Scott ; Quinn, Kristen ; Sundararaj, Kamala ; Wallace, Caroline ; Finnegan, Ryan ; Allen, Patterson ; Mehrotra, Shikhar ; Atkinson, Carl ; Nadig, Satish N. Less -
Description:
Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8| T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.
Subject:
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Article
Source:
Am J Transplant. 22(2):386-401
Pubmed ID:
34714588
Pubmed Central ID:
PMC8813895
Document Type:
Journal Article
Funding:
R01 AI142079/AI/NIAID NIH HHSUnited States/ ; S10 OD018113/OD/NIH HHSUnited States/ ; S10 OD018113/CD/ODCDC CDC HHSUnited States/ ; U01 AI132894/AI/NIAID NIH HHSUnited States/ ; T32 GM008716/GM/NIGMS NIH HHSUnited States/ ; ... More +
R01 AI142079/AI/NIAID NIH HHSUnited States/ ; S10 OD018113/OD/NIH HHSUnited States/ ; S10 OD018113/CD/ODCDC CDC HHSUnited States/ ; U01 AI132894/AI/NIAID NIH HHSUnited States/ ; T32 GM008716/GM/NIGMS NIH HHSUnited States/ ; T32 HL007260/HL/NHLBI NIH HHSUnited States/ ; R01 AI142079 01A1/National Institute of Allergy and Infectious Diseases/ ; 1UO1AI132894-01/NH/NIH HHSUnited States/ Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:5fccc80efb71bbe014a99975a25056c339ec511c2cc8d9ec1342418dca3c1060
Download URL:
https://stacks.cdc.gov/view/cdc/114124/cdc_114124_DS1.pdf
File Type:

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