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

Abstract

Xiaoyin Bu,1,2,* Weifeng Pan,1,* Junhui Wang,1 Liping Liu,1 Zhao Yin,1 Hua Jin,1 Qifa Liu,1 Lei Zheng,3 Haitao Sun,4 Ya Gao,3 Baohong Ping1,2 1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 3Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baohong Ping, Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected] Ya Gao, Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China, Email [email protected]: 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, human leukocyte antigen-G5, gut microbiota, intestinal barrier

Keywords

• acute graft-versus-host disease
• amniotic mesenchymal stem cells
• human leukocyte antigen-g5
• gut microbiota
• intestinal barrier