Functional analysis of costimulatory molecules in oral diseases and their intervention for clinical application

口腔疾病共刺激分子的功能分析及其临床干预应用

• 批准号: 13854021
• 负责人: AZUMA Miyuki
• 金额: $ 69.47万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13854021/
• 关键词: Immunology; Dentistry; Infectious diseases; Cancer; Costimulatory molecules; Oral diseases; Dendritic cells; T lymphocytes; 口腔粘膜疾患; 免疫制御; 歯髄; 粘膜上皮細胞; 免疫; 歯髄炎; 骨吸収; 補助シグナル; 破骨細胞; 細胞間相互作用

We investigated expression and function of costimulatory molecules including PD-1:B7-H1/B7-DC, ICOS:B7h, BTLA, B7-H3, and B7-H3 in oral immune responses and diseases. B7-H1 that is one of ligands for PD-1 was induced on a various inflammatory tissue cells as well as immune cells, whereas expression of B7-DC was limited on activated dendritic cells (DCs) and macrophages. Our results demonstrate the involvement of PD-1:B7-H1 pathway in immune regulation based on the studies from the comparative analyses between expression and clinical features and prognosis in oral lichen planus (OLP) and oral cancer, and in addition, the in vivo treatments with blocking monoclonal antibodies in models of skin contact hypersensitivity and oral cancer. A ligand of ICOS, B7h was less expressed as compared with B7-H1, but was expressed at high levels on endothelial cells in OLP and oral cancer tissues, suggesting the involvement of B7h in lymphocyte infiltration into the tissues.We have established a murine … More pulpitis model using fresh-frozen decalcified hard tissue sections and an immunofluorescence staining and examined dental pulp after dentin exposure. We found that two types of DCs, CD11c^+F4/80^- and CD11c^-F4/80^+, exist in dental pulp. CD11c^+F4/80^- cells located in the pulp-dentin border and expressed constitutively TLR2, TLR4, and CD205. CD11c^-F4/80^+ cells located in the central pulp and were lacking the above molecules. Both types of cells migrated rapidly to the P-D border of treated cusp side, but a part of F4/80^+ cells alone induced a costimulatory molecule CD86. Simultaneously, F4/80^+CD86^+ cells in the regional lymph nodes increased, suggesting the migration of these cells from the pulp. These results suggest that antigen-capture and migration of pulpal DCs may occur and the migrated DCs may induce a consequent adoptive immune response. Our findings provide important information for estimating the healing properties of dental pulp and for developing possible treatments of dental restoration. Less

我们研究了共刺激分子PD-1：B7-H1/B7-DC、ICOS：B7h、BTLA、B7-H3和B7-H3在口腔免疫应答和疾病中的表达和功能。作为PD-1配体之一的B7-H1可在多种炎症组织细胞和免疫细胞上诱导表达，而B7-DC的表达仅限于活化的树突状细胞(DC)和巨噬细胞。通过对口腔扁平苔藓(OLP)和口腔癌组织中PD-1：B7-H1信号转导通路的表达、临床特征和预后的对比分析，以及皮肤接触性超敏反应和口腔癌模型的体内治疗，我们的研究结果表明PD-1：B7-H1通路参与了免疫调节。作为ICOS的配体，B7h在口腔扁平苔藓和口腔癌组织中的表达低于B7-H1，但在口腔扁平苔藓和口腔癌组织中的表达水平较高，提示B7h参与了淋巴细胞对组织的浸润。我们建立了小鼠…更多的牙髓炎模型采用新鲜冷冻脱钙硬组织切片和免疫荧光染色，并检查牙本质暴露后的牙髓。我们发现牙髓中存在CD11c^+F4/80^-和CD11c^-F4/80^+两种类型的DC。CD11c^+F4/80^-细胞位于牙髓-牙本质交界处，主要表达TLR2、TLR4和CD205。CD11c^-F4/80^+细胞位于牙髓中央，缺乏上述分子。两种类型的细胞都能迅速迁移到处理侧的P-D交界处，但部分F4/80^+细胞单独诱导共刺激分子CD86。同时，区域淋巴结内F4/80^+CD86^+细胞增多，提示这些细胞从牙髓中迁移。这些结果提示牙髓DC可能发生了抗原捕获和迁移，迁移的DC可能诱导了随后的过继免疫反应。我们的发现为评估牙髓的愈合特性和开发可能的牙体修复治疗方法提供了重要信息。较少

项目成果

Inducible-costimulator-mediated suppression of human immunodeficiency virus type 1 replication in CD4(+) T lymphocytes.

诱导共刺激物介导的 CD4( ) T 淋巴细胞中人类免疫缺陷病毒 1 型复制的抑制。

• 发表时间: 2004
• 期刊: Virology 325・2
• 作者: Devi;S.S.;Hagiyama;H.;Adachi;T.;Miyasaka;N.;Tsubata;T.;Emori Y. et al.;Nakasako Masayoshi et al.;Zhou X.et al.
• 通讯作者: Zhou X.et al.

A critical role for the programmed death ligand l in fetomaternal tolerance.

程序性死亡配体 l 在母胎耐受中发挥关键作用。

• 发表时间: 2005
• 期刊: J. Exp. Med 202
• 作者: Guleria I;Khousroshahi A;Ansari MJ;Habicht A;Azuma M;Yagita H;Noelle RJ;Coyle A;Mellor AL;Khoury SJ;Sayegh MH
• 通讯作者: Sayegh MH

The effect of recombinant CD80-Adenovirus and interleukin-12 on generation of cytotoxic T lymphocytes against autologous tumour in patients with oral squamous cell carcinoma.

重组CD80腺病毒和白细胞介素12对口腔鳞状细胞癌患者体内抗自体肿瘤的细胞毒性T淋巴细胞产生的影响。

• 发表时间: 2002
• 期刊: Asian J Oral Maxillofac Surg. 14
• 作者: Mogi S;Ebata T;Toda H;Hirano Y;Enomoto S;Azuma M.
• 通讯作者: Azuma M.

PD-1/PD-L1 interaction is essential for induction of regulatory cells by intratracheal delivery of alloantigen.

PD-1/PD-L1 相互作用对于通过气管内输送同种抗原诱导调节细胞至关重要。

• 发表时间: 2004
• 期刊: Transplantation 77
• 作者: Aramaki O;Shirasugi N;Takayama T;Shimazu M;Kitajima M;Azuma M;Ikeda Y;Okumura K;Yagita H;Niimi M.
• 通讯作者: Niimi M.

Shin T: "Cooperative B7-1/2 (CD80/CD86) and B7-DC (PD-L2) costimulation of CD4 T cells independent of the PD-1 receptor."J.Exp.Med.. 198. 31-38 (2003)

Shin T：“B7-1/2 (CD80/CD86) 和 B7-DC (PD-L2) 协同刺激 CD4 T 细胞，不依赖于 PD-1 受体。”J.Exp.Med.. 198. 31-38