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Novel APC Vaccine to Induce Anti-Tumor T cell Immunity

诱导抗肿瘤 T 细胞免疫的新型 APC 疫苗

基本信息

批准号：
6919149
负责人：
MAURIZIO ZANETTI
金额：
$ 30.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6919149
关键词：
B lymphocyte T lymphocyte antigen presenting cell biotechnology cellular immunity cytotoxic T lymphocyte dendritic cells helper T lymphocyte laboratory mouse neoplasm /cancer immunology neoplasm /cancer vaccine transfection tumor antigens vaccine development vector vaccine

项目摘要

DESCRIPTION (provided by the applicant): There are still few reliable and simple methods of vaccination in which the resulting immunity is operationally programmable, restricted to possibly one cell type functioning as antigen producing and antigen presenting cell, and endowed with self-amplifying/self-renewing capacity. This type of vaccine could be of extreme value against cancer.For the past years this laboratory has worked towards developing such a new approach. We established that an adult immunocompetent animal can readily be immunized with a single injection of syngeneic lymphocytes made transgenic in vitro for immunoglobulin (Ig) genes controlled by a B cell specific promoter for targeted expression in B lymphocytes. The Ig genes are themselves engineered to code for heterologous epitopes to confer antigen specificity. Since B lymphocytes are excellent Ig producers and present Ig peptides to CD4 and CD8 T cells very efficiently, transgenic lymphocytes are a novel form of cell vaccine in which endogenous synthesis of antigen and antigen presenting cell (APC) function are ideally combined. We term this process Transgenic Lymphocyte Immunization (TLI). Our preliminary data indicate that these events occur with high fidelity and at high immunological efficiency. TLI lends itself to a robust antigen-specific CD4 and CTL responses with a single injection of as few as 70 transgenic cells. New data provided in the revised application also demonstrate that TLI generates T cell immunity against sub-immungenic epitopes and that the ensuing immunity is highly effective (>85 percent) in tumor protection. The work proposed is built on the hypothesis that B lymphocytes are key to TLI. It is our goal to: (1) elucidate the basic mechanisms of TLI for the induction of antigen-specific CD4 and CD8 responses; (2) compare TLI to vaccination with dendritic cells (DC); and (3) test TLI ability to protect in animal models of tumor. Current vaccines need to be improved with respect to their ability to generate the type of immunity needed to (a) enhance natural defenses or train the immune system to develop new ones, and (b) keep the balance between the tumor growth kinetics and the host immune response in favor of the immune response. We believe that TLI is a simple and effective form of APC vaccine that can meet this need and objectives.

描述（由申请方提供）：仍然存在少数可靠和简单的疫苗接种方法，其中产生的免疫力是可操作编程的，仅限于可能作为抗原产生和抗原呈递细胞的一种细胞类型，并具有自我扩增/自我更新能力。这种类型的疫苗可能对癌症有极大的价值。在过去的几年里，这个实验室一直致力于开发这样一种新的方法。我们确定，成年免疫活性动物可以容易地通过单次注射同基因淋巴细胞进行免疫，所述同基因淋巴细胞在体外针对由B淋巴细胞中靶向表达的B细胞特异性启动子控制的免疫球蛋白（IG）基因进行转基因。IG基因本身被工程化以编码异源表位以赋予抗原特异性。由于B淋巴细胞是优良的IG生产者，并且非常有效地将IG肽呈递给CD 4和CD 8 T细胞，因此转基因淋巴细胞是一种新型的细胞疫苗，其中内源性抗原合成和抗原呈递细胞（APC）功能被理想地结合。我们称这个过程为转基因淋巴细胞免疫（TLI）。我们的初步数据表明，这些事件发生高保真度和高免疫效率。TLI使其自身在单次注射少至70个转基因细胞的情况下产生稳健的抗原特异性CD 4和CTL应答。修订后的申请中提供的新数据还表明，TLI产生针对亚免疫原性表位的T细胞免疫，并且随后的免疫在肿瘤保护中非常有效（> 85%）。所提出的工作是建立在B淋巴细胞是TLI的关键的假设上的。我们的目标是：（1）阐明TLI诱导抗原特异性CD 4和CD 8应答的基本机制;（2）将TLI与树突状细胞（DC）疫苗接种进行比较;和（3）测试TLI在肿瘤动物模型中的保护能力。目前的疫苗需要改进其产生所需免疫类型的能力，以（a）增强天然防御或训练免疫系统以开发新的防御，和（B）保持肿瘤生长动力学和宿主免疫应答之间的平衡以有利于免疫应答。我们相信TLI是一种简单有效的APC疫苗形式，可以满足这一需求和目标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In utero DNA immunisation. Immunity over tolerance in fetal life.

子宫内 DNA 免疫。

DOI：
10.1016/j.vaccine.2004.11.046
发表时间：
2005
期刊：
Vaccine
影响因子：
5.5
作者：
Rizzi,Marta;Gerloni,Mara;Srivastava,AnandS;Wheeler,MatthewC;Schuler,Kilian;Carrier,Ewa;Zanetti,Maurizio
通讯作者：
Zanetti,Maurizio

Plasmid DNA and IL-4 modulate expression of mHC class I and costimulatory molecules in B lymphocytes.

质粒 DNA 和 IL-4 调节 B 淋巴细胞中 mHC I 类和共刺激分子的表达。