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论文题目: Programming of donor T cells using allogeneic delta-like ligand 4-positive dendritic cells to reduce GVHD in mice
英文论文题目: Programming of donor T cells using allogeneic delta-like ligand 4-positive dendritic cells to reduce GVHD in mice
第一作者: Mochizuki, K; Meng, LJ; Mochizuki, I; Tong, Q; He, S; Liu, YN; Purushe, J; Fung, H; Zaidi, MR; Zhang, YY; Reshef, R; Blazar, BR; Yagita, H; Mineishi, S; Zhang, Y
英文第一作者: Mochizuki, K; Meng, LJ; Mochizuki, I; Tong, Q; He, S; Liu, YN; Purushe, J; Fung, H; Zaidi, MR; Zhang, YY; Reshef, R; Blazar, BR; Yagita, H; Mineishi, S; Zhang, Y
联系作者: Zhang, Y (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA.
英文联系作者: Zhang, Y (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA.
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发表年度: 2016
卷: 127
期: 25
页码: 3270-3280
摘要: Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced delta-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naive T cells underwent effector differentiation and produced high levels of interferon gamma (IFN-gamma) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-gamma was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-g led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.
英文摘要: Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced delta-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naive T cells underwent effector differentiation and produced high levels of interferon gamma (IFN-gamma) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-gamma was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-g led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.
刊物名称: BLOOD
英文刊物名称: BLOOD
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学科: Hematology
英文学科: Hematology
影响因子: 13.164
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论文类别: Article
英文论文类别: Article
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