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Immunological and genetic regulations of innate immunity against cutaneous leishmaniasis in mice

小鼠皮肤利什曼病先天免疫的免疫学和遗传调控

基本信息

批准号：
06454202
负责人：
OHTOMO Hiroshi
金额：
$ 4.35万
依托单位：
Jikei University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06454202/
关键词：
cutaneous leishmaniasis Leishmania amazonensis innate immunity resistant gene to infection gene mapping mouse immunology cytokines nerve growth factor 皮膚リーシュマニア感染抵抗性遺伝子マッピング NK細胞肥満細胞 γδT細胞

项目摘要

This study was aimed to understand mechanisms of innate immunity against cutaneous leishmaniasis by examining immunological and genetic regulations in mice infected with Leishmania amazonensis, a pathogen of cutaneous leishmaniasis in the South America. Different strains of mice were subcutaneously inoculated with L.amazonensis promastigotes at the tail base and the size of the skin lesions was measured. Almost all strains of mice such as BALB/c and C57BL/6 exhibited susceptible phenotype to the infection, but SJL/J mice showed strong resistant phenotype without visual lesions. In crossing experiments, both male and female mice of (BALB/c x SJL/J) F1 produced intermediate lesions in size and the backcrossed mice (N2) exhibited susceptible and resistant phenotype at a ratio of approximately 1 : 1, suggesting that the onset of cutaneous lesion is regulated by a single autosomal gene. Mapping of the resistant gene was attempted by analyzing microsatellite DNA polymorphisms in a total of seventy-two N2 mice. The linkage analysis indicated that resistance phenotype of the N2 mice was not linked to Scl1, Scl2 and Lsh/Bcg/Ita gene, which have been reported as the disease control genes for L.major, L.mexicana and L.donovani infection, respectively. The experiments of immunological regulation using mast cell-deficient W/W^V mice, gene-targeted gamma/delta T cell-deficient mice and anti-asialo GM1-inoculated mice suggested that the natural resistance against L.amazonensis infection may be regulated by natural killer cells and gamma/delta T lymphocytes but not by mast cells. Furthermore, intracellular survival of Leishmania in macrophages might be controlled by nerve growth factor, a cytokine involving in inflammatory reactions.

本研究旨在通过检测感染南美皮肤利什曼病病原体亚马逊利什曼原虫的小鼠的免疫和遗传调节，以了解皮肤利什曼病的天然免疫机制。不同品系的小鼠在尾部皮下接种亚马逊乳杆菌前鞭毛体，测量皮损的大小。几乎所有品系的小鼠，如BALB/c和C57BL/6都表现出对感染的易感表型，但SJL/J小鼠表现出较强的抗性表型，而没有视觉损害。在杂交实验中，(BALB/c x SJL/J)F1雄性和雌性小鼠都产生了中等大小的皮损，回交小鼠(N2)表现出大约1：1的易感和抗性表型，表明皮损的发生是由单个常染色体基因调控的。通过对72只N_2小鼠进行微卫星DNA多态分析，试图定位抗性基因。连锁分析表明，N2代小鼠的抗性表型与Scl1、Scl2和LSH/BCG/Ita基因无关，这三个基因分别被报道为主要乳杆菌、墨西哥乳杆菌和多诺瓦尼乳杆菌的致病基因。对肥大细胞缺陷的W/W、V小鼠、基因靶向的Gamma/Delta T细胞缺陷小鼠和抗asialo GM1免疫小鼠的免疫调节实验表明，对亚马孙钩体感染的天然抵抗力可能是由自然杀伤细胞和Gamma/Delta T淋巴细胞调节的，而不是由肥大细胞调节的。此外，巨噬细胞内利什曼原虫的存活可能由神经生长因子控制，神经生长因子是一种参与炎症反应的细胞因子。