2012-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658320摘要：動脈粥狀硬化是一個全球性的健康問題，血液中高密度脂蛋白膽固醇(HDL-C)偏低是動脈粥狀硬化心血管疾病的獨立危險因子。臨床及流行病學研究顯示高密度脂蛋白膽固醇與動脈粥狀硬化心血管疾病呈現明顯的負相關，在台灣的社區研究也顯示HDL-C偏低是動脈粥狀硬化心血管疾病的主要危險因子。因此，醫界一直有興趣研發可以提高HDL-C的策略與方法。HDL具有心血管疾病保護作用主要原因之一是其可以驅動膽固醇逆運轉，膽固醇酯轉移蛋白是膽固醇逆運轉中扮演關鍵角色，抑制膽固醇酯轉移蛋白被認為是一個很可能提高HDL-C預防動脈粥狀硬化心血管疾病的策略。第一個抑制膽固醇酯轉移蛋白的小分子藥物在臨床是驗中因為副作用宣告失敗，即使如此研究人員仍發現抑制膽固醇酯轉移蛋白一些受試者的HDL-C明顯提高也明顯的減少動脈硬化斑塊。我們認為研發疫苗來抑制膽固醇酯轉移蛋白是一個值得嘗試的策略。我們設計一個特殊的膽固醇酯轉移蛋白疫苗，在預備實驗發現可以引發抗體顯著的抑制膽固醇酯轉移蛋白活性進而抑制高脂高膽固醇所誘發之兔子動脈粥狀硬化，這個疫苗並沒有引起腎臟的病理變化。顯示這個疫苗有預防或治療動脈粥狀硬化心血管疾病的潛力，我們的疫苗還有個好處是不需要佐劑即可引起抗體的產生，因此是相對的安全。因此，我們的計劃是開發出這個疫苗來提高HDL-C進而預防及治療動脈粥狀硬化心血管疾病，進而發展成可以為人體可以使用的疫苗或是抗體，進而能夠進入臨床試驗。<br> Abstract: Atherosclerosis is one of the most significant global public health problems. Low plasma level of HDL-cholesterol (HDL-C) is a well established independent risk factors for cardiovascular disease. An inverse association between plasma HDL-C level and the risk of coronary atherosclerosis and cardiovascular mortality has been consistently demonstrated in clinical and epidemiological studies (1-3). An 11-year prospective cohort study in Taiwan community also showing that low HDL cholesterol is the highest attributable risk for coronary heart disease in the general population (4). Because of these, there has been intense interest in developing pharmaceuticals to raise HDL-C levels. The major protective effect of HDL has been attributed to its key role in reverse cholesterol transport (RCT). CETP is a key player of RCT and inhibition of CETP is considered a new approach to coronary artery diseases. The first CETP inhibitors developed to prevent and treat atherosclerotic disease failed due to the off-target non-CETP-related effects; however, investigators found a significant regression of coronary atheroma volume in patients who experienced the largest increase in HDL-C. Using CETP-vaccine to raise antibody against CETP and subsequently inhibit CETP activity provides an alternative way to increase HDL-C. A CETP vaccine (CETi-1) has been developed, which can induce autoantibody production against CETP and raise HDL. However, it failed in phase 2 clinical trial due to poor anti-CETP antibody production and low HDL-C levels. We have designed an anti-CETP vaccine which composes of a clustering epitope of CETP active motif tagged with the human immunoglobulin Fc domain (HuFc). In our preliminary study, this anti-CETP vaccine could elicit high titer of antibody against CETP and inhibited atherosclerosis in rabbits fed high-fat diet. Furthermore, pathological examinations showed no evidence of pathological changes in kidney of the vaccinated rabbits. Suggesting that this anti-CETP vaccine has potential to be developed as vaccine to prevent and treat atherosclerotic disease. Adjuvants are used for generation of strong serological responses to protein antigens in animals; however, most of which cannot be used in human because of deleterious side effects. A HuFc tagged vaccine can be uptaken by antigen-presenting cells mediated by Fc receptor and has prolonged half-lives and is immunogenic in the absence of additional adjuvant. Therefore, the goal of this grant proposal is to develop a HuFc- tagged anti-CETP vaccine that can raise HDL-C and prevent and treat atherosclerotic disease. The vaccine can immunize rabbit without adjuvant and thus can be used in human in the future. The specific aim-1 is to evaluate the efficacy of anti-CETP vaccine in the absence or presence of adjuvant. The titer of anti-CETP antibody, CETP activity and HDL-C level will be compared in rabbits immunized with anti-CETP vaccine in the absence or presence of adjuvant. Aim-2: plasma concentrations of total-C, LDL-C, HDL-C and ApoA1, and development of atherosclerosis will be evaluated in the rabbits. Aim 3: our final goal is to generate humanized anti-CETP vaccine for clinical study.膽固醇脂轉移蛋白高密度脂蛋白膽固醇疫苗粥狀動脈硬化心血管疾病CETPHDL-Cvaccineatherosclerosiscardiovascular disease