CLINICAL TRIAL: IMMUNOLOGIC STUDIES FROM BONE MARROW DONORS AND VOLUNTEERS FOR T

临床试验：来自骨髓捐献者和志愿者的免疫学研究

• 批准号: 7716628
• 负责人: Don J Diamond
• 金额: $ 0.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-20 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716628
• 关键词: Alleles; American; Biopsy; Bone Marrow; Class; Clinical; Clinical Protocols; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Consent Forms; Cytomegalovirus; Ensure; Epitopes; Ethnic Origin; Evaluation; Funding; General Population; Grant; Human; Immune response; Immunologics; In Vitro; Individual; Infection; Institution; Laboratories; Peptides; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Population; Procedures; Proteins; Protocols documentation; Purpose; Research; Research Personnel; Resources; Risk; Source; Techniques; United States; United States National Institutes of Health; Vaccines; Virus; Week; cohort; healthy volunteer; immunogenic; peptide based vaccine; peripheral blood; response; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous results from several laboratories have indicated that the pp65 segament protein from CMV is the major immunogenic protein recognized by individuals who are seropositive for the virus. CTL clones, which recognize pp65 in the context of ten different HLA Class I alleles, have been identified by our laboratory. The repertoire of epitopes that have been defined for these clones are representative of approximately 95% of the ethnic population of the United States. Evaluation of whether these CTL epitopes are predominantly used in the general population requires an analysis of the immunogenecity of the approach of stimulating peripheral blood lymphocytes from HLA-typed individuals who are seropositive for CMV, in a technique in which the free peptide epitope is added at a high concentration to PBMC in microwell cultures. We have used this approach with CTL epitopes specific for pp65 and restricted by HLA A*0201, A*1101,A*2402,A*6901 and B*0702. In each case, we have examined less than five healthy volunteers who are seropositive and have been shown to respond to the CTL epitopes that are specific for the HLA allele, which they express. CD8+CTL, which recognize both peptide loaded and CMV infected targets, are amplified 100-fold in a two-week period. The use of the in vitro stimulation procedure allows a sensitive determination of whether an individual is making a CTL response to CMV, and whether pp65 is a component of that response. We wish to demonstrate that at least five, and if possible, ten randomly chosen individuals will respond to a single epitope, suggesting the potential for a universal response to that epitope from ll individuals who express the same restricting Class I allele. This provides the rationale for an approach to producing vaccine molecules, containing one or more of these epitopes to immunize at-risk individuals against CMV infection. The clinical procedures of obtaining both peripheral blood and biopsy are the central part of the clinical protocol and could be best carried out under the auspices of the GCRC. We have developed cohorts of individuals who express the HLA alleles for which we have epitopes from pp65, and more recently, pp150. We wish to carry out these studies, to characterize all of the major epitopes of CMV pp65 and pp150, which are important in the human immune response to the virus. The purpose for carrying on these studies is to define a peptide-based vaccine that would be applicable to all at-risk individuals. We will also continue to derive new CMV epitopes, to complete our repertoire of epitopes that would ensure as complete a representation as possible of individuals of different ethnicities that make up the American population. There are several consent forms (A-D) which are active for the protocol.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 多个实验室先前的结果表明，来自 CMV 的 pp65 节段蛋白是病毒血清阳性个体识别的主要免疫原性蛋白。 我们的实验室已鉴定出 CTL 克隆，可识别 10 种不同 HLA I 类等位基因中的 pp65。 为这些克隆定义的表位库代表了大约 95% 的美国种族人口。 评估这些 CTL 表位是否主要用于一般人群，需要分析刺激 CMV 血清阳性 HLA 型个体的外周血淋巴细胞的方法的免疫原性，该技术中将游离肽表位添加到微孔培养物中 PBMC 浓度较高。 我们已将这种方法与 pp65 特异性的 CTL 表位结合使用，并受 HLA A*0201、A*1101、A*2402、A*6901 和 B*0702 限制。 在每种情况下，我们都检查了不到五名血清反应呈阳性的健康志愿者，并显示出对他们表达的 HLA 等位基因特有的 CTL 表位有反应。 CD8+CTL 可识别肽负载和 CMV 感染的靶标，在两周内扩增 100 倍。 使用体外刺激程序可以灵敏地确定个体是否对 CMV 产生 CTL 反应，以及 pp65 是否是该反应的组成部分。 我们希望证明，至少五个，如果可能的话，十个随机选择的个体将对单个表位做出反应，这表明表达相同限制性I类等位基因的所有个体对该表位产生普遍反应的潜力。 这为生产包含一个或多个这些表位的疫苗分子的方法提供了基本原理，以使高危个体免受巨细胞病毒感染。 获取外周血和活检的临床程序是临床方案的核心部分，最好在 GCRC 的支持下进行。 我们已经开发了表达 HLA 等位基因的个体群体，我们拥有来自 pp65 以及最近的 pp150 的表位。 我们希望进行这些研究，以表征 CMV pp65 和 pp150 的所有主要表位，这些表位在人类对病毒的免疫反应中很重要。 进行这些研究的目的是确定一种适用于所有高危个体的肽疫苗。 我们还将继续推导出新的 CMV 表位，以完善我们的表位库，以确保尽可能完整地代表构成美国人口的不同种族的个体。 该协议有多种有效的同意书 (A-D)。