Th1-to Th2 shift of HSP65 responses and atherogenesis

描述(由申请人提供 由胞内微生物肺炎衣原体、分枝杆菌引起的感染。和/或幽门螺杆菌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存在争议。我们建议对感染会加速的动脉粥样硬化的免疫变化进行表征。1型辅助性T淋巴细胞(THL)免疫激活局部巨噬细胞(MQ)，杀死细胞内细菌，并可能损害内皮组织，这可能在早期启动损害。以往的研究表明，随着动脉粥样硬化的进展和感染的发生，脾组织中前列腺素E_2释放的MQ(PGE2-MQ)水平升高。由于PGE2是Th1向Th2免疫转变的强大诱导者， PGE2-MQ可能在动脉粥样硬化慢性期的发病机制中起重要作用。穿着这个。分枝杆菌65 kDa热休克蛋白(HSP65)是一种免疫优势抗原，可与其他细菌和哺乳动物的热休克蛋白发生交叉反应。Th1到Th2的转变产生了针对HSP65的抗体，这种抗体可能通过抗原模仿攻击动脉。尽管Th1细胞的发育介导了对结核病的耐药性，但尚不清楚HSP65特异的Thl反应是否也是促动脉粥样硬化的。我们的目标是了解HSP65特异性Th1和Th2反应各自的动脉粥样硬化形成作用以及这种转变的机制。我们将使用高胆固醇血症载脂蛋白E基因敲除(apoE-KO)小鼠和用HSP65免疫的野生型(WT)对照鼠或含有HSP65的热灭活(香港)牛分枝杆菌卡介苗。我们假设HSP65特异性的Th2反应将促进apoE-KO小鼠动脉粥样硬化病变的发展。我们将确定HSP65和甲壳素(Thl佐剂)或明矾(Th2佐剂)免疫是否会对apoE-KO小鼠的动脉粥样硬化病变的发展产生影响。我们将进一步确定过继转移HSP65特异性的Th1细胞或Th2细胞是否会对apoE-KO受者的动脉粥样硬化病变的发展产生影响。用89锶治疗小鼠，破坏了骨髓中的PGE_2-MQ前体，抑制了脾PGE_2-MG的形成。我们假设，这也将导致保留Th1应答而不转移到Th2应答。用89SR处理的小鼠将接受HK-BCG免疫，以确定其对HSP65应答的影响。最后，我们将确定输注HK-BCG治疗的WT供者的FIT-1骨髓细胞是否能恢复89Sr治疗的WT受者从Th1到Th2的转变。

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.