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Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.5 P.392-406


Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway

Author(s):  Yuliang GUO, Siyu SONG, Xiaoxiao DU, Li TIAN, Man ZHANG, Hongmin ZHOU, Zhonghua Klaus CHEN, Sheng CHANG

Affiliation(s):  Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; more

Corresponding email(s):   changsheng2000@126.com

Key Words:  Histone acetylation, Romidepsin (FK228), Skin transplantation, Donor-specific antibody, Unfolded protein response

Yuliang GUO, Siyu SONG, Xiaoxiao DU, Li TIAN, Man ZHANG, Hongmin ZHOU, Zhonghua Klaus CHEN, Sheng CHANG. Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway[J]. Journal of Zhejiang University Science B, 2022, 23(5): 392-406.

@article{title="Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway",
author="Yuliang GUO, Siyu SONG, Xiaoxiao DU, Li TIAN, Man ZHANG, Hongmin ZHOU, Zhonghua Klaus CHEN, Sheng CHANG",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway
%A Yuliang GUO
%A Siyu SONG
%A Xiaoxiao DU
%A Hongmin ZHOU
%A Zhonghua Klaus CHEN
%A Sheng CHANG
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 5
%P 392-406
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100780

T1 - Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway
A1 - Yuliang GUO
A1 - Siyu SONG
A1 - Xiaoxiao DU
A1 - Li TIAN
A1 - Man ZHANG
A1 - Hongmin ZHOU
A1 - Zhonghua Klaus CHEN
A1 - Sheng CHANG
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 5
SP - 392
EP - 406
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100780

Antibody-mediated rejection (AMR) is one of the major causes of graft loss after transplantation. Recently, the regulation of B cell differentiation and the prevention of donor-specific antibody (DSA) production have gained increased attention in transplant research. Herein, we established a secondary allogeneic in vivo skin transplant model to study the effects of romidepsin (FK228) on DSA. The survival of grafted skins was monitored daily. The serum levels of DSA and the number of relevant immunocytes in the recipient spleens were evaluated by flow cytometry. Then, we isolated and purified B cells from B6 mouse spleens in vitro by magnetic bead sorting. The B cells were cultured with interleukin-4 (IL-4) and anti-clusters of differentiation 40 (CD40) antibody with or without FK228 treatment. The immunoglobulin G1 (IgG1) and IgM levels in the supernatant were evaluated by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were conducted to determine the corresponding levels of messenger RNA (mRNA) and protein expression in cultured cells and the recipient spleens. The results showed that FK228 significantly improved the survival of allogeneic skin grafts. Moreover, FK228 inhibited DSA production in the serum along with the suppression of histone deacetylase 1 (HADC1) and HDAC2 and the upregulation of the acetylation of histones H2A and H3. It also inhibited the differentiation of B cells to plasma cells, decreased the transcription of positive regulatory domain-containing 1 (Prdm1) and X-box-binding protein 1 (Xbp1), and decreased the expression of phosphorylated inositol-requiring enzyme 1 α (p-IRE1α), XBP1, and B lymphocyte-induced maturation protein-1 (Blimp-1). In conclusion, FK228 could decrease the production of antibodies by B cells via inhibition of the IRE1α-XBP1 signaling pathway. Thus, FK228 is considered as a promising therapeutic agent for the clinical treatment of AMR.




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