Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8 + T cells and alleviating thymus injury

• Published in: Frontiers in immunology 2024-12, Vol.15, p.1460687
• Main Authors: Wang, Ziwei, Li, Ruiqi, Fu, Weijia, Cheng, Hui, Zhang, Yan, Tang, Gusheng, Yang, Jianmin, Wang, Jianmin, Ni, Xiong
• Format: Article
• Language: English
• Subjects: Animals; anti-CD4 monoclonal antibody; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; CD4 + T cells; CD4 Antigens - immunology; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Chronic Disease; chronic graft-versus-host disease; Disease Models, Animal; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Hematopoietic Stem Cell Transplantation - adverse effects; immune tolerance; Immune Tolerance - drug effects; Immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; thymic recovery; Thymus Gland - drug effects; Thymus Gland - immunology; Transplantation, Homologous
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1460687

Chronic 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. Here, 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. Donor 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. Our 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.