Abstract
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.
概要
目的
探究组蛋白去乙酰化酶(HDAC)抑制剂FK228在体内和体外B细胞抗体产生过程中的生物学作用及其机制。
创新点
首次对FK228在二次同种异体皮肤移植模型中免疫调节作用进行研究, 并初步解析了相关作用机制。
方法
通过建立同种异体小鼠二次皮肤移植模型, 以研究FK228对供者特异性抗体(DSA)的影响。每天监测移植皮肤的存活。通过流式细胞术评估受体血清中DSA水平和脾脏中免疫细胞的数量。然后, 我们通过磁珠分选在体外从B6小鼠脾脏中分离纯化B细胞, 在白细胞介素4(IL-4)和抗CD40共同刺激下培养B细胞, 观察FK228的作用。通过酶联免疫吸附测定(ELISA)评估上清液中的IgG1和IgM水平。进行定量逆转录-聚合酶链反应(RT-qPCR)和蛋白质印迹以确定培养细胞和受体脾脏中浆细胞关键mRNA 表达和IRE1α-XBP1通路蛋白质的相应水平。
结论
FK228处理后可减少二次皮肤移植模型和B细胞体外培养过程中抗体的产生, 并可改善同种异体皮肤移植物的存活。具体作用机制为FK228通过作用于HDAC1和HDAC2, 上调组蛋白H2A和H3的乙酰化水平, 进而抑制抗体合成过程中的IRE1α-XBP1通路。研究结果为临床上治疗AMR和延长移植器官的长期存活提供了新的思路。
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81873511 and 81471587).
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Yuliang GUO, Siyu SONG, Li TIAN, and Man ZHANG performed the experimental research and data analysis. Yuliang GUO, Xiaoxiao DU, and Sheng CHANG wrote and edited the manuscript. Yuliang GUO performed the establishment of animal models. Hongmin ZHOU, Zhonghua Klaus CHEN, and Sheng CHANG contributed to the study design, data analysis, writing and editing of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Yuliang GUO, Siyu SONG, Xiaoxiao DU, Li TIAN, Man ZHANG, Hongmin ZHOU, Zhonghua Klaus CHEN, and Sheng CHANG declare that they have no conflict of interest.
All experiments were conducted according to the animal protection ethics and policies of Huazhong University of Science and Technology (Wuhan, China).
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Guo, Y., Song, S., Du, X. et al. Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway. J. Zhejiang Univ. Sci. B 23, 392–406 (2022). https://doi.org/10.1631/jzus.B2100780
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DOI: https://doi.org/10.1631/jzus.B2100780
Key words
- Histone acetylation
- Romidepsin (FK228)
- Skin transplantation
- Donor-specific antibody
- Unfolded protein response