Role of lymphotoxin in lymphoid organogenesis and contact hypersensitivity.

淋巴毒素在淋巴器官发生和接触性超敏反应中的作用。

基本信息

批准号：
09670478
负责人：
MATSUMOTO Mitsuru
金额：
$ 2.05万
依托单位：
University of Tokushima (1998)Ehime University (1997)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

We have already demonstrated that both lymphotoxin and TNF receptor-I(TNFR-I) play essential roles in the formation of germinal centers (GC) and follicular dendritic cell (FDC) network in the spleen. In the present study, we have investigated the role, of lymphotoxin and TNFR-I in the establishment of spleen FDC and GC structure using reciprocal bone marrow transfer. When lymphotoxin-deficient mice were reconstituted with complement receptor 1 and 2(CR1/2)-deficient bone marrow cells, organized FDC network was identified with anti-CR1/2 monoclonal antibodies, indicating that FDC were derived from lymphotoxin-deficient recipient. Thus, expression of lymphotoxin in the bone marrow-derived cells, but not in the non-bone marrow-derived cells, is required for the maturation of FDC from non-bone marrow precursor cells. Using bone marrow transfer, we were also able to show that formation of FDC network and GC in the spleen are controlled by both lymphotoxin-expressing bone marrow-derived cells and by TNFR-I-expressing non-bone marrow-derived cells.Because lymphotoxin is mainly produced by Th1 type helper T cells, we have also tested in vivo role of lymphotoxin in the induction of contact hypersensitivity, a prototype of delayed-type hypersensitivity reaction, with lymphotoxin-deficient mice. We have found that lymphotoxin-deficient mice exhibit dramatic impaired footpad swelling after antigenic challenge with phenyltrimethylaminoaniline (TMA). Using reciprocal bone marrow transfer, we have demonstrated that impaired contact hypersensitivity in lymphotoxin-deficient mice is due to the impaired function of bone marrow-derived cells in the skin which is essential for the sensitization phase of contact hypersensitivity reaction.These studies clearly demonstrate that lymphotoxin plays an essential role not only in the lymphoid organogenesis but also in the contact hypersensitivity.

我们已经证明淋巴毒素和肿瘤坏死因子受体-I (TNFR-I) 在脾脏生发中心 (GC) 和滤泡树突状细胞 (FDC) 网络的形成中发挥重要作用。在本研究中，我们研究了淋巴毒素和 TNFR-I 在使用相互骨髓移植建立脾 FDC 和 GC 结构中的作用。当用补体受体 1 和 2(CR1/2) 缺陷的骨髓细胞重建淋巴毒素缺陷小鼠时，用抗 CR1/2 单克隆抗体鉴定出有组织的 FDC 网络，表明 FDC 源自淋巴毒素缺陷的受体。因此，来自非骨髓前体细胞的FDC的成熟需要淋巴毒素在骨髓来源的细胞中表达，但不在非骨髓来源的细胞中表达。通过骨髓移植，我们还能够证明脾脏中 FDC 网络和 GC 的形成是由表达淋巴毒素的骨髓来源细胞和表达 TNFR-I 的非骨髓来源细胞控制的。因为淋巴毒素主要由Th1型辅助T细胞产生，我们还在体内测试了淋巴毒素在诱导接触性超敏反应（迟发型超敏反应的原型）中的作用与缺乏淋巴毒素的小鼠发生反应。我们发现，淋巴毒素缺乏的小鼠在用苯基三甲基氨基苯胺（TMA）进行抗原攻击后表现出严重的足垫肿胀受损。通过相互骨髓移植，我们证明了淋巴毒素缺乏小鼠的接触性超敏反应受损是由于皮肤中骨髓来源细胞的功能受损，而这对于接触性超敏反应的致敏阶段至关重要。这些研究清楚地表明淋巴毒素不仅在淋巴器官发生中发挥重要作用，而且在接触性超敏反应中也发挥重要作用。