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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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[1]AragonIV, BarringtonRA, JackowskiS, et al., 2012. The specialized unfolded protein response of B lymphocytes: ATF6α‍-independent development of antibody-secreting B cells. Mol Immunol, 51(3-4):347-355.

[2]BezuL, ChuangAW, LiuP, et al., 2019. Immunological effects of epigenetic modifiers. Cancers, 11(12):1911.

[3]BondarevAD, AttwoodMM, JonssonJ, et al., 2021. Recent developments of HDAC inhibitors: emerging indications and novel molecules. Br J Clin Pharmacol, 87(12):4577-4597.

[4]BuelowR, VeyronP, ClaybergerC, et al., 1995. Prolongation of skin allograft survival in mice following administration of ALLOTRAP. Transplantation, 59(4):455-460.

[5]ChenFY, ChenHF, JiaYJ, et al., 2020. miR-149-5p inhibition reduces Alzheimer’s disease β‍-amyloid generation in 293/APPsw cells by upregulating H4K16ac via KAt8. Exp Ther Med, 20(5):88.

[6]ChoiSC, MorelL, 2020. Immune metabolism regulation of the germinal center response. Exp Mol Med, 52(3):348-355.

[7]ChongAS, 2019. New insights into the development of B cell responses: implications for solid organ transplantation. Hum Immunol, 80(6):378-384.

[8]ClatworthyMR, EspeliM, TorpeyN, et al., 2010. The generation and maintenance of serum alloantibody. Curr Opin Immunol, 22(5):669-681.

[9]Clotet-FreixasS, McEvoyCM, BatruchI, et al., 2020. Extracellular matrix injury of kidney allografts in antibody-mediated rejection: a proteomics study. J Am Soc Nephrol, 31(11):2705-2724.

[10]CobaledaC, SchebestaA, DeloguA, et al., 2007. Pax5: the guardian of B cell identity and function. Nat Immunol, 8(5):463-470.

[11]CrouchEE, LiZY, TakizawaM, et al., 2007. Regulation of AID expression in the immune response. J Exp Med, 204(5):1145-1156.

[12]da CostaTP, El-CheikhMC, CarneiroK, 2020. Epigenetic therapy as a putative molecular target to modulate B cell biology and behavior in the context of immunological disorders. J Immunol Res, 2020:1589191.

[13]DattaSK, 2021. Harnessing tolerogenic histone peptide epitopes from nucleosomes for selective down-regulation of pathogenic autoimmune response in lupus (past, present, and future). Front Immunol, 12:629807.

[14]DudreuilhC, BasuS, ScottàC, et al., 2021. Potential application of T-follicular regulatory cell therapy in transplantation. Front Immunol, 11:612848.

[15]EkronarongchaiS, PalagaT, SaonanonP, et al., 2021. Histone deacetylase 4 controls extracellular matrix production in orbital fibroblasts from Graves’ ophthalmopathy patients. Thyroid, 31(10):1566-1576.

[16]GongJ, WangXZ, WangT, et al., 2017. Molecular signal networks and regulating mechanisms of the unfolded protein response. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 18(1):1-14.

[17]GrootjansJ, KaserA, KaufmanRJ, et al., 2016. The unfolded protein response in immunity and inflammation. Nat Rev Immunol, 16(8):469-484.

[18]GujralP, MahajanV, LissamanAC, et al., 2020. Histone acetylation and the role of histone deacetylases in normal cyclic endometrium. Reprod Biol Endocrinol, 18:84.

[19]HodgkinPD, LeeJH, LyonsAB, 1996. B cell differentiation and isotype switching is related to division cycle number. J Exp Med, 184(1):277-281.

[20]IgarashiK, OchiaiK, Itoh-NakadaiA, et al., 2014. Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. Immunol Rev, 261(1):116-125.

[21]IseW, KurosakiT, 2020. Regulation of plasma cell differentiation. In: Wang JY (Ed.), B Cells in Immunity and Tolerance. Springer, Singapore, p.63-74.

[22]JurkinJ, HenkelT, NielsenAF, et al., 2014. The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells. EMBO J, 33(24):2922-2936.

[23]KassambaraA, RèmeT, JourdanM, et al., 2015. Genomicscape: an easy-to-use web tool for gene expression data analysis. Application to investigate the molecular events in the differentiation of B cells into plasma cells. PLoS Comput Biol, 11(1):e1004077.

[24]KeQ, YangRN, YeF, et al., 2012. Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 13(9):695-706.

[25]KleinU, CasolaS, CattorettiG, et al., 2006. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol, 7(7):773-782.

[26]LiJ, KoernerJ, BaslerM, et al., 2019. Immunoproteasome inhibition induces plasma cell apoptosis and preserves kidney allografts by activating the unfolded protein response and suppressing plasma cell survival factors. Kidney Int, 95(3):611-623.

[27]LoupyA, LefaucheurC, 2018. Antibody-mediated rejection of solid-organ allografts. N Engl J Med, 379(12):‍1150-1160.

[28]LyuX, HuM, PengJT, et al., 2019. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Ther Adv Chronic Dis, 10:1-19.

[29]McCaughanJA, TinckamKJ, 2018. Donor specific HLA antibodies & allograft injury: mechanisms, methods of detection, manifestations and management. Transpl Int, 31(10):1059-1070.

[30]McGeheeAM, DouganSK, KlemmEJ, et al., 2009. XBP-1-deficient plasmablasts show normal protein folding but altered glycosylation and lipid synthesis. J Immunol, 183(6):3690-3699.

[31]MinnichM, TagohH, BöneltP, et al., 2016. Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat Immunol, 17(3):331-343.

[32]MuramatsuM, KinoshitaK, FagarasanS, et al., 2018. Pillars article: class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 102:553-563. J Immunol, 201(9):2530-2540.

[33]NuttSL, HodgkinPD, TarlintonDM, et al., 2015. The generation of antibody-secreting plasma cells. Nat Rev Immunol, 15(3):160-171.

[34]PengLR, YuanZG, LingHB, et al., 2011. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol, 31(23):4720-4734.

[35]PengXP, LiaoGC, SunPH, et al., 2019. An overview of HDAC inhibitors and their synthetic routes. Curr Top Med Chem, 19(12):1005-1040.

[36]PojaniE, BarloccoD, 2021. Romidepsin (FK228), A histone deacetylase inhibitor and its analogues in cancer chemotherapy. Curr Med Chem, 28(7):1290-1303.

[37]RafehiH, KaragiannisTC, El-OstaA, 2017. Pharmacological histone deacetylation distinguishes transcriptional regulators. Curr Top Med Chem, 17(14):1611-1622.

[38]ReimoldAM, IwakoshiNN, ManisJ, et al., 2001. Plasma cell differentiation requires the transcription factor XBP-1. Nature, 412(6844):300-307.

[39]RonD, WalterP, 2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol, 8(7):519-529.

[40]RushJS, LiuM, OdegardVH, et al., 2005. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proc Natl Acad Sci USA, 102(37):13242-13247.

[41]SciammasR, ShafferAL, SchatzJH, et al., 2006. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity, 25(2):225-236.

[42]ShafferAL, Shapiro-ShelefM, IwakoshiNN, et al., 2004. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 21(1):81-93.

[43]Shapiro-ShelefM, LinKI, McHeyzer-WilliamsLJ, et al., 2003. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity, 19(4):607-620.

[44]SheppardEC, MorrishRB, DillonMJ, et al., 2018. Epigenomic modifications mediating antibody maturation. Front Immunol, 9:355.

[45]ShiW, LiaoY, WillisSN, et al., 2015. Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat Immunol, 16(6):663-673.

[46]SriburiR, JackowskiS, MoriK, et al., 2004. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol, 167(1):35-41.

[47]StavnezerJ, GuikemaJEJ, SchraderCE, 2008. Mechanism and regulation of class switch recombination. Annu Rev Immunol, 26:261-292.

[48]SulimanBA, XuDK, WilliamsBRG, 2012. HDACi: molecular mechanisms and therapeutic implications in the innate immune system. Immunol Cell Biol, 90(1):23-32.

[49]TellierJ, ShiW, MinnichM, et al., 2016. Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol, 17(3):323-330.

[50]TorderaRM, Cortés-EriceM, 2021. Role of histone deacetylases in monocyte function in health and chronic inflammatory diseases. In: Pedersen SHF (Ed.), Reviews of Physiology, Biochemistry and Pharmacology. Springer, Cham, p.‍1-47.

[51]TreziseS, NuttSL, 2021. The gene regulatory network controlling plasma cell function. Immunol Rev, 303(1):23-34.

[52]WuXM, CaoL, NieP, et al., 2019. Histone H2A cooperates with RIP2 to induce the expression of antibacterial genes and MHC related genes. Dev Comp Immunol, 101:103455.

[53]YamaguchiT, CubizollesF, ZhangY, et al., 2010. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev, 24(5):455-469.

[54]YangM, ChenG, ZhangX, et al., 2019. Inhibition of class I HDACs attenuates renal interstitial fibrosis in a murine model. Pharmacol Res, 142:192-204.

[55]YangX, YuX, ZhaoZ, et al., 2021. Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(9):746-756.

[56]YeJS, LiJ, ZhouMJ, et al., 2016. Modulation of donor-specific antibody production after organ transplantation by valproic acid: a histone deacetylase inhibitor. Transplantation, 100(11):2342-2351.

[57]YoshidaH, MatsuiT, YamamotoA, et al., 2001. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 107(7):881-891.

[58]ZakzukJ, AcevedoN, HarbH, et al., 2020. IgE levels to Ascaris and house dust mite allergens are associated with increased histone acetylation at key type-2 immune genes. Front Immunol, 11:756.

[59]ZhangX, GuoM, KangYD, et al., 2013. SAHA, an HDAC inhibitor, attenuates antibody-mediated allograft rejection. Transplantation, 96(6):529-537.

[60]ZhaoD, ZouCX, LiuXM, et al., 2020. A UPR-induced soluble ER-phagy receptor acts with VAPs to confer ER stress resistance. Mol Cell, 79(6):963-977.e3.

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