治疗性疫苗的研究进展

治疗性疫苗可克服机体的免疫耐受 ,提高机体的特异性免疫反应 ,对一些目前尚无有效治疗药物的传染性疾病及肿瘤等起到治疗作用。介绍了治疗性疫苗的概况、机理和临床研究的最新进展。     

预防性及治疗性乙型肝炎疫苗的研究进展

乙型病毒性肝炎(viral hepatitis type B,简称乙肝)是一个严重的世界性公共卫生问题,该疾病在健康人群中发病率极高,同时也在慢性乙肝患者中引起极高的死亡率。乙肝是一种可预防的疾病,用于预防的乙肝疫苗经过三代发展,已有安全、有效的疫苗上市,该疫苗的使用使慢性乙肝患者(包括肝细胞性肝癌患者)的发病率急剧下降。但目前尚无清除乙肝患者体内病毒的特效药物,增强机体免疫反应的治疗性疫苗可能是抗病毒药物的替代品。针对乙肝患者的治疗性疫苗正被广泛研究,包含重组蛋白疫苗、DNA疫苗和脂肽疫苗等。现就国内外预防性及治疗性乙肝疫苗的研究进展作一概述。     

治疗性结核病疫苗研究进展

治疗性结核病疫苗主要用于接种已感染结核分枝杆菌的个体,包括化学药物治疗的患者和潜伏感染者。治疗性疫苗可逆转发生在疾病进展期的非保护性免疫反应,使其向Th1型反应发展;能打破机体的免疫耐受,有效激发宿主针对结核分枝杆菌的以抗原为基础的细胞免疫反应,诱发抗原特异性的细胞毒性T淋巴细胞免疫反应,来清除胞内寄生的结核分枝杆菌。治疗性疫苗将有助于防止潜伏结核病的复发;与药物联合使用以提高药物的治疗效果,尤其是针对耐药结核病的治疗。     

肿瘤疫苗的研究进展

作为一种前景光明的肿瘤治疗方式,肿瘤疫苗能帮助机体产生针对肿瘤抗原的特异性免疫应答和长期的免疫记忆来治疗肿瘤,是癌症免疫治疗领域重要的研究方向。目前,肿瘤疫苗按制剂方式主要可以分为四类,即细胞疫苗、病毒疫苗、多肽类疫苗和核酸类疫苗。这些疫苗能通过增强机体内抗肿瘤免疫反应而发挥清除肿瘤细胞、抑制肿瘤生长的功能。该综述将对肿瘤疫苗的作用机制、基础研究与临床试验的最新进展进行讨论,以期为深入理解肿瘤疫苗、开发新型肿瘤疫苗提供有益的参考。     

治疗性疫苗在慢性感染性疾病中的应用

在慢性感染性疾病中,患者往往存在免疫功能异常,表现为药物治疗反应差,于是治疗性疫苗又重新引起了人们的兴趣。治疗性疫苗通过使用新型佐剂,载体,树突细胞过继免疫,同种异体免疫治疗等方法,改善抗原呈递细胞（APC）功能,改善患者免疫耐受情况,从而刺激机体恢复特异性免疫应答,达到根除病原,防止复发的目的。     

乙肝DNA疫苗的研究进展

核酸疫苗包括DNA疫苗和RNA疫苗,目前研究以DNA疫苗为主。乙肝DNA疫苗不仅能诱导机体细胞介导的体液免疫反应,而且还能诱导机体细胞介导的特异性细胞免疫反应,CTL活性增强,在乙型肝炎预防和治疗中具有广阔的应用前景。本文就近几年有关乙肝DNA疫苗的进展作了综述。     

动态

新型结核病疫苗研制成功　德国马普学会传染病生物学研究所研制出一种新型结核病疫苗 ,能够有效增强机体免疫力并能有的放矢地消灭结核病菌。疫苗具有一种特殊的蛋白质分子 ,能够刺激产生T淋巴细胞 ,增强机体免疫系统功能 ,对吞噬细胞内的病菌进行有效攻击。疫苗的有效免疫期为 1 5 0天 ,预计将在一年后进入临床试验。日本开发出早老性痴呆治疗性疫苗　据《日本经济新闻》报道 ,早老性痴呆症 (阿尔茨海默氏症 )是贝塔淀粉样蛋白在脑细胞中沉淀 ,大脑发生萎缩引起的痴呆症。日本国立疗养所中部医院长寿医疗研究中心的原英夫等研究员利用基因…     

EB病毒疫苗的研究进展

EB病毒是一种感染最广泛的人类γ疱疹病毒,与传染性单核细胞增多症、鼻咽癌、Hodgkin’s淋巴瘤以及Burkitt淋巴瘤等发生密切相关。预防和治疗EB病毒相关疾病一直是研究的热点,预防性疫苗主要以病毒包膜糖蛋白gp350为靶点,刺激机体产生抗体以阻止病毒感染;已有多种疫苗进入临床试验,用于预防传染性单核细胞增多症和器官移植后淋巴增殖性紊乱等疾病,并取得良好的试验结果。治疗性疫苗则以病毒复制感染过程中表达的病毒核抗原(EBNAs)和潜伏膜蛋白(LMP1和LMP2)为免疫治疗靶点,刺激机体产生特异性细胞免疫应答,增强细胞毒性T细胞杀伤肿瘤作用。国内外均已有疫苗进入针对鼻咽癌等肿瘤免疫治疗的临床试验,试验结果表明疫苗兼具良好的安全性和免疫原性。本文还综述EB病毒疫苗研究的最新方法、策略和成果,并探讨其中可借鉴的技术和思路,为EB病毒疫苗的研究提供潜在可行的新途径。     

Clin Cancer Res:科学家有望开发出抵御早期乳腺癌的新型疫苗

正免疫系统的反常调节和抑制作用往往会诱发癌症的产生,很多治疗性策略旨在重新激活机体的免疫系统来识别癌细胞并且靶向杀灭癌细胞;近日一项刊登在国际杂志Clinical Cancer Research上的研究报告中,来自莫非特癌症研究中心的研究人员通过研究开发出了一种能够靶向作用乳腺癌细胞表面HER2蛋白的树突细胞疫苗,这种新型疫苗能够安全有效地刺激机体免疫反应,有效逆转早期乳腺癌的发生。     

DNA疫苗机制研究进展

DNA疫苗可全面激活机体的免疫反应,具有安全,热稳定性,价廉等优点,尤其是激活的CTL活性将使之在慢性感染性疾病以及肿瘤治疗领域具有广阔应用前景,但DNA疫苗诱发机体产生免疫反应的机制尚有许多问题有待于搞清,现就DNA疫苗机制及研究进展进行综述。     

Production of therapeutic antibodies with controlled fucosylation

The clinical success of therapeutic antibodies is demonstrated by the number of antibody therapeutics that have been brought to market and the increasing number of therapeutic antibodies in development. Recombinant antibodies are molecular-targeted therapeutic agents and represent a major new class of drugs. However, it is still very important to optimize and maximize the clinical efficacy of therapeutic antibodies, in part to help lower the cost of therapeutic antibodies by potentially reducing the dose or the duration of treatment. Clinical trials using therapeutic antibodies fully lacking core fucose residue in the Fc oligosaccharides are currently underway, and their remarkable physiological activities in humans in vivo have attracted attention as next-generation therapeutic antibody approaches with improved efficacy. Thus, an industrially applicable antibody production process that provides consistent yields of fully non-fucosylated antibody therapeutics with fixed quality has become a key goal in the successful development of next-generation therapeutic agents. In this article, we review the current technologies for production of therapeutic antibodies with control of fucosylation of the Fc N-glycans.Key words: fucose, non-fucosylated, therapeutic antibodies, ADCC, FcγRIIIa     

Patients' ranking of therapeutic factors in group analysis

The aim of this research is to assess which therapeutic factors are of greatest importance to patients in group analytic psychotherapy, and whether the patients' characteristics and the phase of the group process influenced their evaluation of therapeutic factors. The Yalom's group therapeutic factors questionnaire was filled out by 66 patients, members of small groups conducted according to group analytic principles. The average scores for each therapeutic factor were subsequently ranked by importance to the patients and related to their age, sex, education, previous psychotherapeutic experience and phase of group process. Self-understanding was the highest-ranking therapeutic factor for the patients (average score 21.32 +/- 0.04 out of 25 maximum), whereas identification was the lowest ranking factor (15.88 +/- 0.06 in average). Group therapeutic factors were scored higher by women, patients up to 30 years of age, high-school graduates, and those with previous psychotherapeutic experience. Self-understanding seems to be the most important therapeutic factor in group analysis, emphasizing the importance of appropriate selection of patients for group analysis in order to utilize therapeutic factors the best.     

Photochemical release of methotrexate from folate receptor-targeting PAMAM dendrimer nanoconjugate

Nanoparticle (NP)-based targeted drug delivery involves cell-specific targeting followed by a subsequent therapeutic action from the therapeutic carried by the NP system. NPs conjugated with methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (DHFR) localized in cytosol, have been under investigation as a delivery system to target cancer cells to enhance the therapeutic index of methotrexate, which is otherwise non-selectively cytotoxic. Despite improved therapeutic activity from MTX-conjugated NPs in vitro and in vivo, the therapeutic action of these conjugates following cellular entry is poorly understood; in particular it is unclear whether the therapeutic activity requires release of the MTX. This study investigates whether MTX must be released from a nanoparticle in order to achieve the therapeutic activity. We report herein light-controlled release of methotrexate from a dendrimer-based conjugate and provide evidence suggesting that MTX still attached to the nanoconjugate system is fully able to inhibit the activity of its enzyme target and the growth of cancer cells.     

A novel delivery platform for therapeutic peptides

Although many peptides have therapeutic effects against diverse disease, their short half-lives in vivo hurdle their application as drug candidates. To extend the short elimination half-lives of therapeutic peptides, we developed a novel delivery platform for therapeutic peptides using an anti-hapten antibody and its corresponding hapten. We selected cotinine because it is non-toxic, has a well-studied metabolism, and is physiologically absent. We conjugated WKYMVm-NH₂, an anti-sepsis therapeutic peptide, to cotinine and showed that the conjugated peptide in complex with an anti-cotinine antibody has a significantly improved in vivo half-life while retaining its therapeutic efficacy. We suggest that this novel delivery platform for therapeutic peptides will be very useful to develop effective peptide therapeutics.     

The Impact of Legal Coercion on the Therapeutic Relationship in Adult Schizophrenia Patients

The quality of the therapeutic relationship between psychiatric patients and their attending physicians plays a key role in treatment success. We hypothesize that mandatory treatment is negatively associated with the quality of the therapeutic relationship. In a cross-sectional study design, data on psychopathological symptom load (as captured with the Brief Psychiatric Rating Scale) and on the quality of the therapeutic relationship (as measured with the Scale to Assess the Therapeutic Relationship) were collected from 113 adult male psychiatric patients and 35 attending physicians. Patients belonged to one of three groups: self-referred or involuntarily admitted patients from general psychiatry wards or patients from medium secure forensic psychiatric units. On average, self-referred patients rated the quality of the therapeutic relationship significantly more positive than did involuntarily admitted patients in general psychiatry wards. Forensic psychiatric patients, on average, gave an intermediate rating of the quality of the therapeutic relationship. There was no association between patients’ ratings and physicians’ ratings of the quality of the therapeutic relationship. Patients’ ratings of the quality of the therapeutic relationship were inversely related to symptom severity in general and hostility in particular. Ratings of the quality of the therapeutic relationship are not associated with patients’ legal status but rather with patients’ symptoms of hostility.     

高强度聚焦超声可治疗区域的仿真研究

数值仿真不同治疗参数条件下高强度聚焦超声(high intensity focused ultrasound,HIFU)可治疗区域的变化,对HIFU治疗剂量的确定具有重要的指导意义。本文采用Westervelt方程的近似式,结合Pennes生物热传导方程,以离体猪肝组织为例,在考虑组织声学特性对HIFU焦域温度场影响的条件下,通过时域有限差分法(finite difference time domain,FDTD)对HIFU焦域温度场进行仿真研究。研究结果表明,照射时间越长,组织声学特性的影响就越明显;焦点处的最高温升相同时,可治疗区域的大小差异较小;声强越大,形成可治疗区域所需的时间也越短;当声强一定时,随着照射时间的增加,可治疗区域的长、短轴长度均呈非线性增加;在相同可治疗区域的长轴或短轴长度一定时,输入声强和照射时间呈负相关。     

核心岩藻糖基化控制在治疗性抗体研究中的应用

对于人类许多疾病,抗体已成为了一种很重要的治疗制剂。如何进一步提高抗体的效能,是目前研究的主要热点之一。在抗体治疗过程中,抗体依赖性细胞介导的细胞毒作用(antibody dependent cellular cytotoxicity,ADCC)被认为是治疗性抗体临床疗效中一个重要的治疗功能。抗体恒定区Fc片段(crystalline fragment)的糖基化对ADCC起着至关重要的作用,尤其是抗体恒定区的核心岩藻糖基化。近些年来,很多研究报告表明,去除或降低岩藻糖基化的治疗性抗体不论在体内还是在体外都表现出更高的效能。这主要是由于去除或降低岩藻糖基化的治疗性抗体相对于岩藻糖基化的抗体,可以在更低浓度下通过与FcγRIIIa的高亲和力而表现出较强的ADCC作用。因此,去除或降低岩藻糖基化抗体的应用有望成为提高下一代治疗性抗体效能的有效手段。在此综述中,我们主要讨论了控制治疗性抗体恒定区岩藻糖基化的重要性及当前去除或降低岩藻糖基化治疗性抗体的生产控制方法。     

Attitudes of Obstetric and Gynecologic Residents Toward Abortion

As a follow-up to Wolf''s study of attitudes of obstetrical housestaff toward therapeutic abortion,⁵ the attitudes of 48 obstetrical residents in the San Francisco Bay area were evaluated by questionnaire and structured interview. Specific issues studied were: (1) Willingness to perform therapeutic abortion, (2) impact of therapeutic abortion on Resident Training Program, (3) attitudes toward different operational procedures, and (4) preferred physician-patient relationship with therapeutic abortion patients. Findings suggest that although there is recognition and acceptance by most residents of the social need for therapeutic abortion, considerable ambivalence persists.     

核移植与治疗性克隆

核移植与治疗性克隆在畜牧业生产以及生物医学上具有广阔和诱人的应用前景。文章分析指出卵母细胞质量与供核细胞重新编程是影响体细胞核移植效率及克隆动物异常的主要因素,阐述了治疗性克隆所面临的一些基本问题及出路：治疗性克隆以核移植技术为基础,核移植所面临的一些问题也直接影响着治疗性克隆的临床应用;核移植胚胎干细胞分离培养效率的高低以及向重要功能细胞定向分化是治疗性克隆的前提;成体干细胞可用于一些重大疾病的治疗,但不能完全替代克隆性治疗;伦理问题也阻碍治疗性克隆的发展。核移植及治疗性克隆技术要想尽快更好地应用于临床和造福于人类,需要不断完善各技术环节和加强一些基础理论的研究。Abstract: Nuclear transfer and therapeutic cloning have widespread and attractive prospects in animal agriculture and biomedical applications. We reviewed that the quality of oocytes and nuclear reprogramming of somatic donor cells were the main reasons of the common abnormalities in cloned animals and the low efficiency of cloning and showed the problems and outlets in therapeutic cloning, such as some basic problems in nuclear transfer affected clinical applications of therapeutic cloning. Study on isolation and culture of nuclear transfer embryonic stem (ntES) cells and specific differentiation of ntES cells into important functional cells should be emphasized and could enhance the efficiency. Adult stem cells could help to cure some great diseases, but could not replace therapeutic cloning. Ethics also impeded the development of therapeutic cloning. It is necessary to improve many techniques and reinforce the research of some basic theories, then somatic nuclear transfer and therapeutic cloning may apply to agriculture reproduction and benefit to human life better.     

The prediction of immunogenicity of therapeutic proteins

Immunogenicity of therapeutic proteins is a nightmare for industrials because induced antibodies can neutralize the therapeutic activity and provoke autoimmune symptoms. It was believed that sequence humanization would be sufficient to tackle these problems but multiple clinical examples now demonstrate that humanization does not suffice to abrogate immune responses. In order to predict immunogenicity of therapeutic proteins, different approaches have been developed, among which the most relevant ones are based on the evaluation of the response of na?ve CD4 T lymphocytes specific for therapeutic proteins. Other approaches also exist or are in development. This review is the state of art in the different technologies that are proposed to predict immunogenicity of therapeutic proteins.