Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro.
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.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Jiangsu, PR China. lihmd@163.com
Kailin
K
Xu
Chaohong
C
Li
Xiuying
X
Pan
Bing
B
Du
D053330:4-1BB Ligand / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000379:methods; D046528:Chimerism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007165:Immunosuppression Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous / Q000379:methods; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000187:drug effects*
D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9