Th1-to Th2 shift of HSP65 responses and atherogenesis

HSP65 反应的 Th1 向 Th2 转变和动脉粥样硬化形成

• 批准号: 6663819
• 负责人: YOSHIMI SHIBATA
• 金额: $ 28.1万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663819
• 关键词: Mycobacterium; atherosclerosis; bacterial proteins; bone marrow transplantation; chitin; cross immunity; gene targeting; genetically modified animals; heat shock proteins; helper T lymphocyte; immunomodulators; immunopathology; immunoregulation; laboratory mouse; passive immunization; prostaglandin E

DESCRIPTION (provided by applicant Infections caused by the intracellular organisms, Chlamydia pneumoniae, Mycobacterium sp. and/or Helicobacter pylori, have been implicated as co-risk factors in atherosclerosis, but their exact roles in disease progression remain controversial. We propose to characterize the immunological shifts in atherosclerosis that would be accelerated by the infections. Type 1 helper T lymphocyte- (Thl-) immunity activates local macrophages (MQ) that kill the intracellular bacteria and also potentially damage endothelial tissue, which could initiate lesions at the early stages. Previous studies suggest that splenic prostaglandin E2-releasing MQ (PGE2-MQ) levels are increased with the progression of atherosclerosis and in infections. Since PGE2 is a powerful inducer of the Thl to Th2 immune shift, PGE2-MQ could make a major contribution to the pathogenesis of chronic stages of atherosclerosis. In this. regard, much attention has been directed to mycobacterial 65kDa-heat shock protein (HSP65), an immunodominant antigen having cross-reactivity with other bacterial and mammalian HSPs. The Thl-to-Th2 shifts generate antibodies against HSP65 that potentially attack arteries through antigenic mimicry. Although the development of the Thl cells mediates resistance to tuberculosis, it remains unclear whether HSP65-specific Thl responses are also pro-atherogenic. Our goals are to understand the respective atherogenic roles of HSP65-specific Thl and Th2 responses as well as the mechanism of the shifts. We will employ hypercholesterolemic apolipoprotein E-knockout (apoE-KO) mice and wild type (WT) controls immunized with HSP65 or heat-killed (HK) M. bovis BCG containing HSP65. We hypothesize that HSP65-specific Th2 responses will enhance atherogenic lesion development in apoE-KO mice. We will determine if immunization with HSP65 and chitin, a Thl adjuvant, or alum, a Th2 adjuvant, will have an effect on atherogenic lesion development in apoE-KO mice. We will further determine if adoptive transfer of HSP65- specific Thl cells or Th2 cells will have an effect on atherogenic lesion development in apoE-KO recipients. Treatment of mice with 89Sr destroys PGE2-MQ precursors in the bone marrow and suppresses the formation of splenic PGE2-MG. We hypothesize that this will also result in retention of the Thl responses without a shift to a Th2 response. Mice treated with 89Srwill receive HK-BCG immunization to determine the effect on response to HSP65. Finally, we will determine if transfusion of fit-1 +marrow cells from HK-BCG treated WT donors will restore the Thl-to-Th2 shifts in 89Sr-treated WT recipients.

描述（由申请人提供 由细胞内微生物肺炎衣原体、分枝杆菌属和/或幽门螺杆菌引起的感染已被认为是动脉粥样硬化的共同危险因素，但它们在疾病进展中的确切作用仍有争议。 我们建议描述动脉粥样硬化中的免疫学变化，这种变化会被感染加速。1型辅助性T淋巴细胞（Thl-）免疫激活局部巨噬细胞（MQ），其杀死细胞内细菌并且还潜在地损伤内皮组织，这可能在早期阶段引发病变。 以往的研究表明，脾前列腺素E2释放MQ（PGE 2-MQ）水平增加与动脉粥样硬化和感染的进展。 由于PGE 2是Th 1至Th 2免疫转变的强有力诱导剂， PGE 2-MQ可能在动脉粥样硬化慢性阶段的发病机制中起重要作用。在这方面因此，分枝杆菌65 kDa热休克蛋白（HSP 65）作为一种与其他细菌和哺乳动物HSPs具有交叉反应性的免疫显性抗原，受到了广泛关注。Th 1至Th 2的转变产生针对HSP 65的抗体，其通过抗原模拟潜在地攻击动脉。虽然Thl细胞的发展介导对结核病的抗性，但仍不清楚HSP 65特异性Thl应答是否也是促动脉粥样硬化的。 我们的目标是了解HSP 65特异性Th 1和Th 2应答各自的致动脉粥样硬化作用以及这种转变的机制。我们将采用高胆固醇血症载脂蛋白E基因敲除（apoE-KO）小鼠和野生型（WT）对照，用HSP 65或热灭活（HK）M免疫。含HSP 65的牛卡介苗。 我们假设HSP 65特异性Th 2应答将增强apoE-KO小鼠动脉粥样硬化病变的发展。 我们将确定用HSP 65和几丁质（一种Th 1佐剂）或明矾（一种Th 2佐剂）免疫是否对apoE-KO小鼠中致动脉粥样硬化病变的发展有影响。我们将进一步确定HSP 65特异性Th 1细胞或Th 2细胞的过继转移是否对apoE-KO受体中的致动脉粥样硬化病变发展具有影响。 用89 Sr治疗小鼠破坏骨髓中的PGE 2-MQ前体并抑制脾PGE 2-MG的形成。 我们假设这也将导致Thl应答的保留而不转变为Th 2应答。用89 Sr处理的小鼠将接受HK-BCG免疫以确定对HSP 65应答的影响。 最后，我们将确定输注来自HK-BCG治疗的WT供体的fit-1 +骨髓细胞是否会恢复89 Sr治疗的WT受体中Th 1至Th 2的转变。