Therapeutic Effects of HLA-G5 Overexpressing hAMSCs on aGVHD After Allo-HSCT: Involving in the Gut Microbiota at the Intestinal Barrier

Xiaoyin Bu; Weifeng Pan; Junhui Wang; Liping Liu; Zhao Yin; Hua Jin; Qifa Liu; Lei Zheng; Haitao Sun; Ya Gao; Baohong Ping

doi:10.2147/JIR.S420747

Therapeutic Effects of HLA-G5 Overexpressing hAMSCs on aGVHD After Allo-HSCT: Involving in the Gut Microbiota at the Intestinal Barrier

J Inflamm Res. 2023 Aug 24:16:3669-3685. doi: 10.2147/JIR.S420747. eCollection 2023.

Authors

Xiaoyin Bu^#^{1

2}, Weifeng Pan^#¹, Junhui Wang¹, Liping Liu¹, Zhao Yin¹, Hua Jin¹, Qifa Liu¹, Lei Zheng³, Haitao Sun⁴, Ya Gao³, Baohong Ping^{1

2}

Affiliations

¹ Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
² Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
³ Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
⁴ Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People's Republic of China.

^# Contributed equally.

Abstract

Background: Acute graft-versus-host disease (aGVHD) initiated by intestinal barrier dysfunction and gut microbiota dysbiosis, remains one of the main obstacles for patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) to achieve good prognosis. Studies have suggested that mesenchymal stem cells (MSCs) can suppress immune responses and reduce inflammation, and human leukocyte antigen-G5 (HLA-G5) plays an important role in the immunomodulatory effects of MSCs, but very little is known about the potential mechanisms in aGVHD. Thus, we explored the effect of HLA-G5 on the immunosuppressive properties of human amnion MSCs (hAMSCs) and demonstrated its mechanism related to the gut microbiota at the intestinal barrier in aGVHD.

Methods: Patients undergoing allo-HSCT were enrolled to detect the levels of plasma-soluble HLA-G (sHLA-G) and regulatory T cells (Tregs). Humanized aGVHD mouse models were established and treated with hAMSCs or HLA-G5 overexpressing hAMSCs (ov-HLA-G5-hAMSCs) to explore the mechanism of HLA-G5 mediated immunosuppressive properties of hAMSCs and the effect of ov-HLA-G5-hAMSCs on the gut microbiota at the intestinal barrier in aGVHD.

Results: The plasma levels of sHLA-G on day +30 after allo-HSCT in aGVHD patients were lower than those in patients without aGVHD, and the sHLA-G levels were positively correlated with Tregs percentages. ov-HLA-G5-hAMSCs had the potential to inhibit the expansion of CD3+CD4+ T and CD3+CD8+ T cells and promote Tregs differentiation, suppress proinflammatory cytokine secretion but promote anti-inflammatory cytokines release. Besides, ov-HLA-G5-hAMSCs also could reverse the intestinal barrier dysfunction and gut microbiota dysbiosis in aGVHD.

Conclusion: We demonstrated that HLA-G might work with Tregs to create a regulatory network together to reduce the occurrence of aGVHD. HLA-G5 mediated hAMSCs to exert higher immunosuppressive properties in vivo and reverse the immune imbalance caused by T lymphocytes and cytokines. Furthermore, HLA-G5 overexpressing hAMSCs could restore gut microbiota and intestinal barriers, thereby ameliorating aGVHD.

Keywords: acute graft-versus-host disease; amniotic mesenchymal stem cells; gut microbiota; human leukocyte antigen-G5; intestinal barrier.