title: Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models.
abstract: In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs(ICOS-EGFP)) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCs(ICOS-EGFP), MSCs, MSCs(EGFP), ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4(+) T-cell apoptosis and proliferation, and Th1/Th2/Th17 effecter cell polarization were evaluated. In the C57BL/6 → CB6F1 HSCT model, the long-term survival in the MSC(ICOS-EGFP) group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + ICOS-Ig groups (42.86 ± 8.36%, p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSC(ICOS-EGFP)-treated group were confirmed in the C57BL/6 → BALB/c HSCT model. In both HSCT models, the low mortality in the MSC(ICOS-EGFP) group was associated with lower incidence and severity of acute GvHD. Treatment with MSCs(ICOS-EGFP) induced more CD4(+) T-cell apoptosis compared with that in the GvHD group. The effect on CD4(+) T cells was shown as early as day 2 and maintained until day 14 (p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs(ICOS-EGFP) were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSC(ICOS-EGFP) group. The MSCs(ICOS-EGFP) could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-γt expression. Our results showed that injection of MSCs(ICOS-EGFP) is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.
authors.affiliation: Institute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.forename: Xiao-Chen
authors.initials: XC
authors.lastname: Bao
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhang
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D015996:Survival Rate; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000172:deficiency / Q000378:metabolism
chemical_list: D016207:Cytokines; D060889:Inducible T-Cell Co-Stimulator Protein; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse