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: 6945782
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945782
• 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）

项目成果

Persistent inactivation of macrophage cyclooxygenase-2 in mycobacterial pulmonary inflammation.

分枝杆菌肺部炎症中巨噬细胞环氧合酶-2 的持续失活。

• DOI: 10.1165/rcmb.2008-0230oc
• 发表时间: 2009
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Shinohara,Tsutomu;Pantuso,Traci;Shinohara,Shizuka;Kogiso,Mari;Myrvik,QuentinN;Henriksen,RuthAnn;Shibata,Yoshimi
• 通讯作者: Shibata,Yoshimi

Role of PPARγ in COX-2 activation in mycobacterial pulmonary inflammation.

PPARγ 在分枝杆菌肺部炎症中 COX-2 激活中的作用。

• DOI: 10.1007/s10753-012-9486-x
• 发表时间: 2012
• 期刊: Inflammation
• 影响因子: 5.1
• 作者: Kogiso,Mari;Shinohara,Tsutomu;Dorey,CKathleen;Shibata,Yoshimi
• 通讯作者: Shibata,Yoshimi

Heat-killed BCG induces biphasic cyclooxygenase 2+ splenic macrophage formation--role of IL-10 and bone marrow precursors.

热灭活的 BCG 诱导双相环氧合酶 2 脾巨噬细胞形成——IL-10 和骨髓前体的作用。

• DOI: 10.1189/jlb.1205737
• 发表时间: 2006
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Shibata,Yoshimi;Gabbard,Jon;Yamashita,Makiko;Tsuji,Shoutaro;Smith,Mike;Nishiyama,Akihito;Henriksen,RuthAnn;Myrvik,QuentinN
• 通讯作者: Myrvik,QuentinN

Differential subcellular localization of COX-2 in macrophages phagocytosing heat-killed Mycobacterium bovis BCG.

COX-2 在吞噬热灭活牛分枝杆菌 BCG 的巨噬细胞中的差异亚细胞定位。

• DOI: 10.1152/ajpcell.00346.2006
• 发表时间: 2007
• 期刊: American journal of physiology. Cell physiology
• 作者: Yamashita,Makiko;Tsuji,Shoutaro;Nishiyama,Akihito;Myrvik,QuentinN;Henriksen,RuthAnn;Shibata,Yoshimi
• 通讯作者: Shibata,Yoshimi

Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners.

称为模拟真菌的膳食几丁质颗粒可通过 Toll 样受体 2/CD14 和性别依赖性方式改善结肠炎。

• DOI: 10.1128/iai.00006-19
• 发表时间: 2019
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Louis,Patricia;Mercer,Brian;Cirone,AikoM;Johnston,Christina;Lee,ZacharyJ;Esiobu,Nwadiuto;Li,Zhongwei;Wei,Jianning;Dorey,CKathleen;Shibata,Yoshimi;Nan,Changlong
• 通讯作者: Nan,Changlong