Development of novel therapies of hematologic malignancies based on the functional modulation of the OX40/gp34 system

基于OX40/gp34系统功能调节的血液恶性肿瘤新疗法的开发

• 批准号: 12357005
• 负责人: UCHIYAMA Takashi
• 金额: $ 27.08万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12357005/
• 关键词: OX40; gp34; GVHD; GVL; gp34; 造血器腫瘍; 樹状細胞

Role of TRAF3 in OX40 signalingWe previously reported that OX40 signaling leads to NF-κB activation via TRAF2 and TRAF5. TRAF3 also binds to the cytoplasmic domain of OX40 but functiions rather negatively to suppress NF-κB activation. In the present study we found that overexpression of TRAF3 did not affect NIK- or IKKα-medicated NF-κB activation and that both N-terminus and C-terminus deletion mutants of TRAF3 have inhibitory effect. These results indicate that TRAF3 suppresses NF-κB activation at the pathway between TRAF2 and NIK, which is not necessarily due to competitive inhibition of binding between OX40 and TRAF2.gp34 expressed on endothelial cells provides T cells with costimulatory signalsPurified normal human CD4+ T cells did not proliferate in response to immobilized anti-CD3 mAb but showed vigorous proliferation in the coexistence of human umbilical vein endothelial cells (HUVEC). Addition of anti-gp34 mAb maredly inhibited this response, indicating that the OX40/gp34 syste … More m plays a major role in costimulation of CD4+ T cells by endothelial cells.Correlation of peripheral blood OX40+ T cells with chronic graft-versus-host disease (cGVHD)We studied whether the expression of OX40 is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplant. Peripheral blood mononuclear cells from a total of 22 patients after day 100 were subjected to multi-color flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+ T cells were significantly higher in patients with cGVHD than those without Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and at the onset closely correlated with the therapeutic response. These results indicated that serial measurement of OX40+ T cells is quite useful for predicting the onset as well as therapeutic response of cGVHD.Possible role of the OX40/gp34 in the leukemogenesis of ATLWe studied the relationship between OX40 signals and apoptosis of ATL cells. ATL constitutively express OX40 and became resistant to anti-Fas-induced apoptosis when cocultured MMCE-gp34 while coculture with MMCE-mock had no effects. Thus, it is suggested that ATL cells receive favorable signals for survival through the OX40/gp34 system.Signaling of gp34 induces vascular endothelial cells to produce RANTESWe searched for genes that were induced or upregulated by gp34 signaling in HUVECs to define its downstream biological events. HUVECs expressing high levels of gp34 were stimulated with recombinant soluble OX40 or mock control and subjected to analysis using cDNA expression arrays. We found that a CC chemokine RANTES is one of such inducible genes. Namely, gp34 signaling induces expression of RANTES at both mRNA and protein levels in HUVECs and suggest a possible link between the OX40/gp34 system and RANTES during the process of T cell adhension to endothelial cells and subsequent extravasation. Less

TRAF 3在OX 40信号转导中的作用我们以前报道过OX 40信号转导通过TRAF 2和TRAF 5激活NF-κB。TRAF 3也与OX 40的胞质结构域结合，但其功能相当负面，抑制NF-κB活化。在本研究中，我们发现TRAF 3的过表达不影响NIK或IKKα介导的NF-κB活化，并且TRAF 3的N端和C端缺失突变体都具有抑制作用。这些结果表明TRAF 3在TRAF 2和NIK之间的通路上抑制NF-κB活化，在内皮细胞上表达的gp 34为T细胞提供了共刺激信号。纯化的正常人CD 4 + T细胞对固定的抗-TRAF 2抗体没有反应性增殖。CD 3单克隆抗体，但在人脐静脉内皮细胞（HUVEC）的共存显示出旺盛的增殖。加入抗gp 34单克隆抗体几乎不能抑制这种反应，这表明OX 40/gp 34系统可能是一种免疫抑制剂。 ...更多信息 外周血OX 40 ~+ T细胞与慢性移植物抗宿主病（cGVHD）的相关性研究我们研究了OX 40的表达是否与异基因造血干细胞移植患者cGVHD的发生有关。在第100天后，对来自总共22名患者的外周血单核细胞进行多色流式细胞术。cGVHD患者外周血中OX 40 + CD 4+和OX 40 + CD 8 + T细胞百分比均显著高于非cGVHD患者。OX 40/gp 34在ATL白血病发生中的作用我们研究了OX 40信号与ATL细胞凋亡的关系。ATL组成型表达OX 40，并对抗Fas诱导的细胞凋亡时，共培养MMCE-gp 34，而与MMCE-mock共培养没有影响。因此，提示ATL细胞通过OX 40/gp 34系统接收有利于存活的信号，gp 34信号诱导血管内皮细胞产生RANTES我们在HUVECs中寻找被gp 34信号诱导或上调的基因以确定其下游生物学事件。用重组可溶性OX 40或模拟对照刺激表达高水平gp 34的HUVEC，并使用cDNA表达阵列进行分析。我们发现CC趋化因子RANTES是这样的诱导基因之一。也就是说，gp 34信号在HUVECs中诱导RANTES在mRNA和蛋白水平上的表达，并且表明在T细胞粘附于内皮细胞和随后的外渗过程中，OX 40/gp 34系统和RANTES之间可能存在联系。少

项目成果

Akifumi Takaori-Kondo: "Both amino-and carboxyl-terminal domain of TRAF3 negatively regulate NF-kB activation induced by OX40 signaling"Biochemical and Biophysical Research Communications. 272. 856-863 (2000)

Akifumi Takaori-Kondo：“TRAF3 的氨基和羧基末端结构域均负向调节 OX40 信号传导诱导的 NF-kB 激活”《生物化学和生物物理研究通讯》。

Kotani A.: "Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CC15"Immunology Letters. 84. 1-7 (2002)

Kotani A.：“gp34（OX40 配体）的信号传导诱导血管内皮细胞产生 CC 趋化因子 RANTES/CC15”免疫学快报。

Kotani A.: "Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine PANTES/CC15"Immunology Letters. 84. 1-7 (2002)

Kotani A.：“gp34（OX40 配体）的信号传导诱导血管内皮细胞产生 CC 趋化因子 PANTES/CC15”免疫学快报。

Kunitomi A.: "Vascular endothelial cells provide T cells with constimulatory signals via the OX0/gp34 system"J. Leukocyte Biol. 67. 111-118 (2000)

Kunitomi A.：“血管内皮细胞通过 OX0/gp34 系统为 T 细胞提供刺激信号”J.

Kotani A.: "Correlation of peripheral blood OX40^+ (CD134^+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation"Blood. 98(10). 3162-3164 (2001)

Kotani A.：“接受同种异体造血干细胞移植的患者外周血 OX40^ (CD134^) T 细胞与慢性移植物抗宿主病的相关性”血液。