Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury
BackgroundChronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGV...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1460687/full |
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| author | Ziwei Wang Ruiqi Li Weijia Fu Hui Cheng Yan Zhang Gusheng Tang Jianmin Yang Jianmin Wang Xiong Ni |
| author_facet | Ziwei Wang Ruiqi Li Weijia Fu Hui Cheng Yan Zhang Gusheng Tang Jianmin Yang Jianmin Wang Xiong Ni |
| author_sort | Ziwei Wang |
| collection | DOAJ |
| description | BackgroundChronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGVHD after allogenic hematopoietic cell transplantation (HCT) has become a major challenge.Materials and methodsHere, we used a representative cGVHD model with the donor C57BL/6 to recipient BALB/c combination. Post-HCT, mice were treated with IgG or anti-CD4 monoclonal antibody. The severity of cGVHD was assessed by evaluating symptoms of cGVHD and histopathology examination (H&E) of target organs. Thymus gland damage and defects of the negative selection were assessed by analyzing the CD4+CD8+ double-positive thymocytes, cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs). Immunotolerance of CD8+ T cells was assessed by detecting the expression of CD80, PD-1, GRAIL and IL-7Rα. Long-term cellular and humoral immunity associated with graft-versus-leukemia (GVL) effects were evaluated through detecting the percentage of CD4+ T cells, IgG, IgM and IgA concentrations, and performing tumor challenge experiment.ResultsDonor CD8+ T cells caused thymic epithelial cells damage and impaired negative selection in recipients, leading to generation of autoreactive T cells and causing cGVHD. Anti-CD4 mAb treatment promoted immune incompetence of thymus-infiltrating CD8+ T cells, facilitated recovery of CD4+CD8+ thymocytes and regeneration mTECs, and preserved negative-selection, but had no effects on the long-term cellular immunity and humoral immunity, resulting in preservation of GVL effect.ConclusionOur results indicate that anti-CD4 mAb therapy early post-HCT allows thymus recovery by inducing the immune tolerance of thymus infiltrated CD8+ T cells, thereby alleviating thymic epithelial cells damage, preserving negative selection, and preserving long-term GVL effect at the same time. |
| format | Article |
| id | doaj-art-eccd5d2fab364137a917f232b309a797 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-eccd5d2fab364137a917f232b309a7972024-12-24T06:36:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-12-011510.3389/fimmu.2024.14606871460687Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injuryZiwei WangRuiqi LiWeijia FuHui ChengYan ZhangGusheng TangJianmin YangJianmin WangXiong NiBackgroundChronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGVHD after allogenic hematopoietic cell transplantation (HCT) has become a major challenge.Materials and methodsHere, we used a representative cGVHD model with the donor C57BL/6 to recipient BALB/c combination. Post-HCT, mice were treated with IgG or anti-CD4 monoclonal antibody. The severity of cGVHD was assessed by evaluating symptoms of cGVHD and histopathology examination (H&E) of target organs. Thymus gland damage and defects of the negative selection were assessed by analyzing the CD4+CD8+ double-positive thymocytes, cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs). Immunotolerance of CD8+ T cells was assessed by detecting the expression of CD80, PD-1, GRAIL and IL-7Rα. Long-term cellular and humoral immunity associated with graft-versus-leukemia (GVL) effects were evaluated through detecting the percentage of CD4+ T cells, IgG, IgM and IgA concentrations, and performing tumor challenge experiment.ResultsDonor CD8+ T cells caused thymic epithelial cells damage and impaired negative selection in recipients, leading to generation of autoreactive T cells and causing cGVHD. Anti-CD4 mAb treatment promoted immune incompetence of thymus-infiltrating CD8+ T cells, facilitated recovery of CD4+CD8+ thymocytes and regeneration mTECs, and preserved negative-selection, but had no effects on the long-term cellular immunity and humoral immunity, resulting in preservation of GVL effect.ConclusionOur results indicate that anti-CD4 mAb therapy early post-HCT allows thymus recovery by inducing the immune tolerance of thymus infiltrated CD8+ T cells, thereby alleviating thymic epithelial cells damage, preserving negative selection, and preserving long-term GVL effect at the same time.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1460687/fullchronic graft-versus-host diseaseCD4 + T cellsanti-CD4 monoclonal antibodythymic recoveryimmune tolerance |
| spellingShingle | Ziwei Wang Ruiqi Li Weijia Fu Hui Cheng Yan Zhang Gusheng Tang Jianmin Yang Jianmin Wang Xiong Ni Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury Frontiers in Immunology chronic graft-versus-host disease CD4 + T cells anti-CD4 monoclonal antibody thymic recovery immune tolerance |
| title | Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury |
| title_full | Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury |
| title_fullStr | Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury |
| title_full_unstemmed | Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury |
| title_short | Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8+ T cells and alleviating thymus injury |
| title_sort | anti cd4 monoclonal antibody prevents chronic graft versus host disease in mice by inducing immune tolerance of cd8 t cells and alleviating thymus injury |
| topic | chronic graft-versus-host disease CD4 + T cells anti-CD4 monoclonal antibody thymic recovery immune tolerance |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1460687/full |
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