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

• Published in: Journal of inflammation research Vol. 16; pp. 3669 - 3685
• Main Authors: Bu, Xiaoyin, Pan, Weifeng, Wang, Junhui, Liu, Liping, Yin, Zhao, Jin, Hua, Liu, Qifa, Zheng, Lei, Sun, Haitao, Gao, Ya, Ping, Baohong
• Format: Journal Article
• Language: English
• Published: Dove Medical Press Limited 30.09.2023; Dove; Dove Medical Press
• Subjects: acute graft-versus-host disease; amniotic mesenchymal stem cells; Analysis; gut microbiota; Health aspects; Hematopoietic stem cells; Histocompatibility antigens; HLA histocompatibility antigens; human leukocyte antigen-g5; Immune response; Inflammation; intestinal barrier; Measuring instruments; Microbiota (Symbiotic organisms); Original Research; Prognosis; Scientific equipment and supplies industry; T cells; Transplantation; United States; China
• ISSN: 1178-7031; 1178-7031
• DOI: 10.2147/JIR.S420747

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, human leukocyte antigen-G5, gut microbiota, intestinal barrier