Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro

• Published in: International journal of hematology Vol. 86; no. 1; pp. 84 - 90
• Main Authors: Xu, Kailin, Li, Chaohong, Pan, Xiuying, Du, Bing
• Format: Journal Article
• Language: English
• Published: Tokyo Springer 01.07.2007; Springer Nature B.V
• Subjects: 4-1BB Ligand - drug effects; 4-1BB Ligand - immunology; Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Bone Marrow Transplantation - methods; Chimerism; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Hematologic and hematopoietic diseases; Immunosuppression - methods; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Survival Analysis; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; Transplantation, Homologous - methods; Tumor Necrosis Factor Receptor Superfamily, Member 9 - drug effects; Graft-versus-host disease; Immunopathology; Hematology; Ligand; Stem cell; Hematopoietic cell; Homograft; Bone marrow transplantation; Graft versus host reaction; In vitro; Immune tolerance; Costimulatory receptor 4-1BB; Bone marrow; Graft; Anti-CD137L MoAbs
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1532/IJH97.A10613

Engagement of the TCR without appropriate costimulation will result in the inability of T-cells to respond to the alloantigen as described earlier. We made a further investigation into the effect of relieving graft-versus-host disease (GVHD) and its mechanism in mice by blocking CD137-CD137L pathway in vitro. Responder cells (spleen cells) from BALB/C donor mice (H-2d) were incubated with stimulator cells (spleen cells) from C57BL/6 recipient mice (H-2b), with or without anti-CD137L monoclonal antibodies (MoAbs). Donor bone marrow cells plus mixed lymphocyte culture (MLC) T-cells were transplanted into lethally irradiated C57BL/6 mice. C57BL/6 mice were divided into 3 groups: group A (allogeneic bone marrow transplantation control group), group B (cyclosporine + methotrexate group), and group C (donor T-cells were treated with anti-CD137L MoAbs). The percentage of CD3+CD4+ and CD3+CD8+ T-cells were detected by flow cytometry, and the levels of cytokines (IFN-gamma, interleukin [IL]-2, IL-10, IL-4) by reverse-transcriptase polymerase chain reaction. The incidence of GVHD in group C was 70%, while the incidence of GVHD was 100% in group A and group B. The survival rate of group C was higher than that of group A and B, and the median survival time was longer than that of group A and B (P < .01). Clinical symptoms and histological signs of GVHD in group C were the mildest among all 3 groups. The percentage of CD3+CD8+T-cells in group C was lower than that in group A and B (P < .01). The levels of IFN-gamma in group C were markedly lower than those in group A and B (P < .01), and the levels of IL-10 in group C were significantly higher than those in group A and B (P < .01). The results suggest that treatment of donor T-cells by anti-CD137L MoAbs in vitro may relieve GVHD, thereby improve the survival time and survival rate of recipient mice, which might be related to the increased TH1 cytokine (IFN-gamma) and decreased TH2 cytokine (IL-10) as well as the reduced CD3+CD8+T-cells.