Immune regulation by OX40/OX40 ligand system

OX40/OX40配体系统的免疫调节

• 批准号: 11670311
• 负责人: ISHII Naoto
• 金额: $ 2.3万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670311/
• 关键词: OX40 ligand; OX40L-deficient mice; Experimental autoimmune encephalomyelitis (EAE); Leishmania Major感染症; OX40; 抗原提示細胞

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L mAb, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-IgM stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice, engendered apparent suppression of the recall reaction of T cells primed with both protein- and allo-antigens and a significant reduction in KLH-specific IgG production. The impaired T-cell-priming was also accompanied by a concomitant reduction of both Th1 and Th2 cytokines. Furthermore, antigen presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.Furthermore, we examined the effect of OX40L-deficiency or blockade of OX40-OX40L interaction in pathogenesis of experimental autoimmune encephalitis (EAE), which is a mouse model for human multiple sclerosis. OX40L-deficient and MGP34-treated mice showed less symptoms and rapid recovery during EAE as compared with wild type or control Ab-treated mice. These results suggest that OX40L may be functionally involved in the pathogenesis of autoimmune diseases such as EAE.

OX40是一种重要的共刺激分子，表达于活化的T细胞上，在体外对T细胞的激活起重要作用。然而，OX40与其配体OX40L相互作用的体内功能意义仍不清楚。为了研究OX40L在体内免疫应答中的作用，我们建立了OX40L缺陷小鼠和一种封闭的抗OX40L单抗MGP34。经CD40和抗IgM刺激后，脾B细胞表达OX40L，而仅CD40结扎能诱导树突状细胞表达OX40L。OX40L缺陷和MGP34处理的小鼠，导致蛋白质和同种抗原同时启动的T细胞的召回反应明显受到抑制，KLH特异性免疫球蛋白的产生显著减少。受损的T细胞启动也伴随着Th1和Th2细胞因子的减少。此外，来自突变小鼠的抗原提呈细胞(APC)显示出内在的APC功能受损，证明了OX40L在T细胞激活的启动和效应阶段的重要性。综上所述，这些结果提供了令人信服的证据，证明表达在APC上的OX40L在活体抗原特异性T细胞反应中发挥关键作用。此外，我们还研究了OX40L缺乏或阻断OX40-OX40L相互作用在实验性自身免疫性脑炎(EAE)发病机制中的作用。与野生型或对照抗体处理的小鼠相比，OX40L缺陷和MGP34处理的小鼠在EAE期间表现出较少的症状和快速的恢复。这些结果提示OX40L可能在自身免疫性疾病如EAE的发病机制中起重要作用。

项目成果

Kazuko Murata et.al.: "Impairment of Antigen-presenting Cell Function in Mice Lacking Expression of OX40 Ligand"J. Exp. Med.. 191. 365-374 (2000)

Kazuko Murata 等人：“缺乏 OX40 配体表达的小鼠中抗原呈递细胞功能的损伤”J.

Onodera J,Nagata T,Fujihara K,Ohuchi M,Ishii N, et al.: "Expression of OX40 and OX40 ligand (gp34) in the normal and myasthenic thymus"Acta Neurol Scand.. 102・4. 236-243 (2000)

Onodera J、Nagata T、Fujihara K、Ohuchi M、Ishii N 等：“正常胸腺和肌无力胸腺中 OX40 和 OX40 配体 (gp34) 的表达” Acta Neurol Scand.. 102・4 (2000) ）

Murata,K.,Ishii,N.,Takano,H. et.al.: "Impairment of antigen presenting cell function in mice lacking expression of OX40 ligand."J.Exp.Med.. 191・2. 365-374 (2000)

Murata, K.、Ishii, N.、Takano, H. 等：“缺乏 OX40 配体表达的小鼠中抗原呈递细胞功能受损。”J.Exp.Med.. 191・2。 2000)

Kikuchi K,Kawasaki Y,Ishii N, et al.: "Suppression of thymic development by the dominant-negative form of Gads"Int.Immunol.,. (in press). (2001)

Kikuchi K、Kawasaki Y、Ishii N 等人：“Gad 的显性失活形式对胸腺发育的抑制”Int.Immunol.,。

Murata, K., Ishii, N., Takano, H., Miura S, Nodhlovu LC, Nose M, Noda T, and Sugamura K.: "Impairment of antigen presenting cell function in mice lacking expression of OX40 ligand."J.Exp.Med.. Vol.191. 365-374 (2000)

Murata, K.、Ishii, N.、Takano, H.、Miura S、Nodhlovu LC、Nose M、Noda T 和 Sugamura K.：“缺乏 OX40 配体表达的小鼠中抗原呈递细胞功能受损。”