阿尔茨海默症疫苗研究和乙肝疫苗临床免疫评价体系研究
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摘要
疫苗能够调动机体的免疫反应,对抗原作出适宜的免疫应答,从而达到治疗疾病的目的。针对许多慢性疾病目前尚无有效治疗药物,而疫苗由于特异性好、成本低等优点,成为许多慢性疾病治疗领域研究的热点。
阿尔茨海默症(AD)是一种神经系统的慢性急病,其病因是由于p淀粉样蛋白(Aβ)在大脑中沉积,对神经纤维产生毒性作用,使其损伤而导致疾病的发生。抗Aβ42的蛋白疫苗由于其能诱导高滴度抗体而被确认对AD有减轻病情的效果,但是由于其引起了针对于Aβ42的T细胞侵润脑部导致临床实验失败。如何保持高滴度抗体并且抑制T细胞的炎性反应是Aβ42疫苗改进的方向。本论文第一部分根据本实验室发现蛋白与DNA共免疫可以诱导调节性T细胞,抑制效应T细胞的炎症反应同时不影响抗体滴度,在抗原形式上采用Aβ42共免疫疫苗作为新型AD疫苗。研究中我们证明了Aβ42共免疫疫苗能诱导高水平的针对于Aβ42的抗体,同时能够很好地抑制CD4+T细胞介导的炎症反应。这种免疫治疗方法不仅可以改善AD模型小鼠的认知和学习能力,减轻脑部淀粉样蛋白的沉积,还可以有效地抑制T细胞介导的炎症反应,阻止CD4+T细胞侵润中枢神经系统。我们除了对抗原的形式进行了改进探索,同时还对佐剂的改进进行了初步的研究,采用免疫抑制剂和增强型免疫佐剂同时进行筛选,用共免疫体系验证加入佐剂后的效果。在对佐剂的研究中,发现加入免疫抑制剂并不能够维持共免疫的免疫抑制效果,而增强型免疫佐剂能够维持共免疫的免疫抑制效果。我们在流感模型中进行了增强型佐剂的筛选,确定了小分子化合物尼扎替有丁有较强的免疫增强作用,并在共免疫体系中进行了验证,初步确定了该佐剂用于AD共免疫疫苗的可能性。
Aβ42蛋白疫苗失败于炎症副反应,同时也显示出目前几乎所有治疗性疫苗研发中的一个薄弱环节,就是治疗性疫苗的评价只侧重于病情改善和病理评价,不能从免疫学角度去预测疫苗可能造成的效果和副反应,针对这一情况,本论文第二部分以乙肝治疗性疫苗—乙克(YIC)小临床实验为依托,通过检测特异性T细胞的免疫反应来建立疫苗的临床免疫学评价体系。T细胞功能主要通过其分泌的细胞因子实现,因此在本研究中检测CD4+T和CD8+T表达的共21种细胞因子,分析其表达水平、临床表型变化和免疫次数的相关性,结果发现疫苗组与安慰剂组的ALT和HBV DNA水平在抗病毒药物的干预下二者没有区别,但是在免疫学上,特别是CD4和CD8的活化状态上有了区别于其它两组的差异,推测乙肝治疗性疫苗可能是通过激活APC细胞,活化CD4+T细胞,使其在四免后大量的表达活化性的细胞因子,处于活化状态,进而辅助激活CD8+T细胞,增强其杀伤功能起到免疫学作用的,从而为接下来大规模的临床实验提供了可能的检测方案和检测指标,以期初步建立乙肝治疗性疫苗的临床检测系统。
综上所述,本论文对于AD研究了一种新型的治疗性疫苗,在动物实验中证明了疫苗的治疗效果和安全性,并用尼扎替丁为佐剂对疫苗进行了进一步改进；同时以乙克小临床实验为依托,检测免疫前后T细胞免疫反应的变化,初步寻找到了临床实验中与疫苗免疫相关的检测指标。通过这两部分工作,为治疗性疫苗的研发和进入临床提供了新的视点。
Vaccine could treat diseases via stimulating body's own immune responses, and regulating specific immune aims to elicit appropriate responses against pathogens. Currently, there is no effective drug treatment against various chronic infections and related diseases, but the therapeutic vaccine technology, which has good specficity and low cost, presents a great opportunity to solve the problems.
Alzheimer's disease (AD) is a one of nervous system chronic illness. The most important pathological hallmark is formation of extracellular senile plaques (SP) containing the peptide β amyloid (Aβ). It is reported that vaccinations using Aβ protein could well clear the Aβ deposits in murine models. However, at the same time, this vaccination induced some patients appearing meningoencephalitis because of CD4+T cells activations. To reduce T cell activation, but yet remain the high level of anti-Aβ42antibody is a great challenge in the field of immunology. In this study, we demonstrated that a co-immunization of AP42could not only induce high level of antibodies against the Aβ42, but also inhibit its T cell-mediated inflammation. This protocol could improves cognitive deficits significantly in an AD model and the induced immunity does not lead the CD4+T cell-mediated infiltrations in CNS. Therefore, co-immunization strategy elicited a protective response against the AD without pathogenesis may lead to the development of a safety immunotherapeutic means against AD in humans. Besides the immunization protocol, we also improved the adjuvant for AD vaccine. We tried both of the immunosuppressive and enhanced adjuvant as the co-immunization adjuvant. We found that immunosuppressive adjuvant could not improve the co-immunization function, but the enhanced adjuvant had this function. So we screen the adjuvant in influenza vaccine, found Nizatidine, a small molecular compound, could stimulate immune response. The results also showed that Nizatidine was able to confirm the co-immunization affection and be used in the AD co-immunization vaccine.
Back to investigation of the reason for Aβ42protein vaccine failure in the clinical trial due to the inflammatory responses, one of the main reasons was that no systematic immune analysis particularly in cell mediated responses in the most of therapeutic vaccine research. Now cell based clinical immunological evaluations become a major hurdle against development of therapeutic vaccines. Therefore, the establishment of a comprehensive clinical evaluation system for therapeutic vaccines is an urgent need. In the second part of this paper, we participated in a small clinical trial of ongoing therapeutic HBV vaccine-YIC, to establish a clinical evaluation system analysis of detecting the T cell specific immune responses. One of which, is the T cell multi-function analysis and realized by the secretion of cytokines of a single T cell. In this study, we examined that totally21kinds of cytokine expressions within the population of CD4+T and CD8+T, and further correlating between the level of cytokine expressions and clinical outcomes over the course of vaccinations. We observed that the levels of ALT and HBV DNA were significant difference between the group of YIC and placebo in immune responses, particularly in the activations of CD4and CD8. CD4+T cells in the YIC group were exhibited a significant activation after four immunizations, whereas the CD8+T cells were activated after six immunizations. These results provided the first evident to show that a therapeutic vaccination could modulate host cell mediated responses. The evaluation system could be further explored to become a clinical analysis means to assist evaluations for the development of therapeutic vaccines during clinical trials.
In summary, we developed a novel therapeutic vaccine based on the co-immunization technology against AD. This vaccine provides effective treatment against AD but yet not adverse effects, and used Nizatidine as adjuvant to improve the co-immunization vaccine. To fill the gap between immunology and clinical evaluation for therapeutic vaccine, we developed a clinical evaluation system based on analysis of multi-functional T cells during vaccinations.
阿尔茨海默症(AD)是一种神经系统的慢性急病,其病因是由于p淀粉样蛋白(Aβ)在大脑中沉积,对神经纤维产生毒性作用,使其损伤而导致疾病的发生。抗Aβ42的蛋白疫苗由于其能诱导高滴度抗体而被确认对AD有减轻病情的效果,但是由于其引起了针对于Aβ42的T细胞侵润脑部导致临床实验失败。如何保持高滴度抗体并且抑制T细胞的炎性反应是Aβ42疫苗改进的方向。本论文第一部分根据本实验室发现蛋白与DNA共免疫可以诱导调节性T细胞,抑制效应T细胞的炎症反应同时不影响抗体滴度,在抗原形式上采用Aβ42共免疫疫苗作为新型AD疫苗。研究中我们证明了Aβ42共免疫疫苗能诱导高水平的针对于Aβ42的抗体,同时能够很好地抑制CD4+T细胞介导的炎症反应。这种免疫治疗方法不仅可以改善AD模型小鼠的认知和学习能力,减轻脑部淀粉样蛋白的沉积,还可以有效地抑制T细胞介导的炎症反应,阻止CD4+T细胞侵润中枢神经系统。我们除了对抗原的形式进行了改进探索,同时还对佐剂的改进进行了初步的研究,采用免疫抑制剂和增强型免疫佐剂同时进行筛选,用共免疫体系验证加入佐剂后的效果。在对佐剂的研究中,发现加入免疫抑制剂并不能够维持共免疫的免疫抑制效果,而增强型免疫佐剂能够维持共免疫的免疫抑制效果。我们在流感模型中进行了增强型佐剂的筛选,确定了小分子化合物尼扎替有丁有较强的免疫增强作用,并在共免疫体系中进行了验证,初步确定了该佐剂用于AD共免疫疫苗的可能性。
Aβ42蛋白疫苗失败于炎症副反应,同时也显示出目前几乎所有治疗性疫苗研发中的一个薄弱环节,就是治疗性疫苗的评价只侧重于病情改善和病理评价,不能从免疫学角度去预测疫苗可能造成的效果和副反应,针对这一情况,本论文第二部分以乙肝治疗性疫苗—乙克(YIC)小临床实验为依托,通过检测特异性T细胞的免疫反应来建立疫苗的临床免疫学评价体系。T细胞功能主要通过其分泌的细胞因子实现,因此在本研究中检测CD4+T和CD8+T表达的共21种细胞因子,分析其表达水平、临床表型变化和免疫次数的相关性,结果发现疫苗组与安慰剂组的ALT和HBV DNA水平在抗病毒药物的干预下二者没有区别,但是在免疫学上,特别是CD4和CD8的活化状态上有了区别于其它两组的差异,推测乙肝治疗性疫苗可能是通过激活APC细胞,活化CD4+T细胞,使其在四免后大量的表达活化性的细胞因子,处于活化状态,进而辅助激活CD8+T细胞,增强其杀伤功能起到免疫学作用的,从而为接下来大规模的临床实验提供了可能的检测方案和检测指标,以期初步建立乙肝治疗性疫苗的临床检测系统。
综上所述,本论文对于AD研究了一种新型的治疗性疫苗,在动物实验中证明了疫苗的治疗效果和安全性,并用尼扎替丁为佐剂对疫苗进行了进一步改进；同时以乙克小临床实验为依托,检测免疫前后T细胞免疫反应的变化,初步寻找到了临床实验中与疫苗免疫相关的检测指标。通过这两部分工作,为治疗性疫苗的研发和进入临床提供了新的视点。
Vaccine could treat diseases via stimulating body's own immune responses, and regulating specific immune aims to elicit appropriate responses against pathogens. Currently, there is no effective drug treatment against various chronic infections and related diseases, but the therapeutic vaccine technology, which has good specficity and low cost, presents a great opportunity to solve the problems.
Alzheimer's disease (AD) is a one of nervous system chronic illness. The most important pathological hallmark is formation of extracellular senile plaques (SP) containing the peptide β amyloid (Aβ). It is reported that vaccinations using Aβ protein could well clear the Aβ deposits in murine models. However, at the same time, this vaccination induced some patients appearing meningoencephalitis because of CD4+T cells activations. To reduce T cell activation, but yet remain the high level of anti-Aβ42antibody is a great challenge in the field of immunology. In this study, we demonstrated that a co-immunization of AP42could not only induce high level of antibodies against the Aβ42, but also inhibit its T cell-mediated inflammation. This protocol could improves cognitive deficits significantly in an AD model and the induced immunity does not lead the CD4+T cell-mediated infiltrations in CNS. Therefore, co-immunization strategy elicited a protective response against the AD without pathogenesis may lead to the development of a safety immunotherapeutic means against AD in humans. Besides the immunization protocol, we also improved the adjuvant for AD vaccine. We tried both of the immunosuppressive and enhanced adjuvant as the co-immunization adjuvant. We found that immunosuppressive adjuvant could not improve the co-immunization function, but the enhanced adjuvant had this function. So we screen the adjuvant in influenza vaccine, found Nizatidine, a small molecular compound, could stimulate immune response. The results also showed that Nizatidine was able to confirm the co-immunization affection and be used in the AD co-immunization vaccine.
Back to investigation of the reason for Aβ42protein vaccine failure in the clinical trial due to the inflammatory responses, one of the main reasons was that no systematic immune analysis particularly in cell mediated responses in the most of therapeutic vaccine research. Now cell based clinical immunological evaluations become a major hurdle against development of therapeutic vaccines. Therefore, the establishment of a comprehensive clinical evaluation system for therapeutic vaccines is an urgent need. In the second part of this paper, we participated in a small clinical trial of ongoing therapeutic HBV vaccine-YIC, to establish a clinical evaluation system analysis of detecting the T cell specific immune responses. One of which, is the T cell multi-function analysis and realized by the secretion of cytokines of a single T cell. In this study, we examined that totally21kinds of cytokine expressions within the population of CD4+T and CD8+T, and further correlating between the level of cytokine expressions and clinical outcomes over the course of vaccinations. We observed that the levels of ALT and HBV DNA were significant difference between the group of YIC and placebo in immune responses, particularly in the activations of CD4and CD8. CD4+T cells in the YIC group were exhibited a significant activation after four immunizations, whereas the CD8+T cells were activated after six immunizations. These results provided the first evident to show that a therapeutic vaccination could modulate host cell mediated responses. The evaluation system could be further explored to become a clinical analysis means to assist evaluations for the development of therapeutic vaccines during clinical trials.
In summary, we developed a novel therapeutic vaccine based on the co-immunization technology against AD. This vaccine provides effective treatment against AD but yet not adverse effects, and used Nizatidine as adjuvant to improve the co-immunization vaccine. To fill the gap between immunology and clinical evaluation for therapeutic vaccine, we developed a clinical evaluation system based on analysis of multi-functional T cells during vaccinations.
引文
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