Immune Response to Clostridium difficile

对艰难梭菌的免疫反应

• 批准号: 6877172
• 负责人: Ciaran P Kelly
• 金额: $ 34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877172
• 关键词: Clostridium difficile; antitoxins; bacterial antigens; bacterial toxicology; bacterial toxins; cellular immunity; clinical research; colitis; detoxification; diarrhea; disease /disorder proneness /risk; enzyme linked immunosorbent assay; hamsters; host organism interaction; human subject; humoral immunity; immunoglobulin G; immunoglobulin M; microorganism growth; patient oriented research; recombinant proteins; relapse /recurrence

DESCRIPTION (provided by applicant): Clostridium difficile is the most common cause of infectious diarrhea in hospital patients and is associated with substantial morbidity, mortality and financial cost. The longterm goal of this project is to assist in the development and clinical application of novel non-antibiotic agents to prevent and treat C. difficile-associated diarrhea and colitis. The central hypothesis of this proposal is that host factors, especially the immune response to C. difficile antigens, play a major role in determining the clinical outcome of C. difficile infection. We will perform a prospective cohort study of 150 subjects with C. difficile-associated diarrhea (CDAD) to examine each of the following three hypotheses: Hypothesis 1: lmmune responses to both C. difficile toxin A and toxin B are instrumental in protecting against recurrent CDAD. Our recent studies have shown that a serum IgG response to C. difficile toxin A is evident in subjects that are protected against symptomatic or recurrent CDAD. In this aim we will determine whether humoral and cell-mediated immune responses to toxin B, immune responses to toxin A recombinant peptides and/or toxin neutralizing activity are also associated with protection. Hypothesis 2: Risk for recurrent CDAD can be predicted based on clinical parameters and or anti-toxin antibody measurement. Based on our previous study of patients with CDAD (derivation cohort) we have developed prediction rules with >80% accuracy in predicting recurrence. In this aim we will prospectively test these rules in the 150 subjects recruited for Specific Aim 1 (validation cohort). Once validated these tools can be used in clinical practice and in research studies to identify high-risk patients that are most likely to benefit from measures to prevent recurrent C. difficile infection. Hypothesis 3: lmmune responses to C. difficile Surface Layer Protein (SLP) can protect against colonization and/or CDAD. Previous studies of the immune response to C. difficile have focused almost exclusively on anti-toxin antibodies. C. difficile surface layer protein (SLP) is the predominant surface protein in C. difficile, has been characterized recently at the molecular level and appear to act as a bacterial adhesin. Our preliminary data indicate that an immune response to C. difficile surface layer protein may be protective. In this aim we will compare humoral and cell-mediated immune responses to purified and recombinant C. difficile SLP in subjects with a single episode of CDAD, those with recurrent disease and in disease and healthy controls. We will also determine whether vaccination against C. difficile SLP can prevent colonization by C. difficile and/or C. difficile associated ileo-cecitis in hamsters. These specific aims are designed to advance further our knowledge of the immunobiology of C. difficile toxin-induced diarrhea and the mechanisms of immune protection in humans.

描述（由申请人提供）：艰难梭菌是医院患者感染性腹泻的最常见原因，与大量的发病率、死亡率和经济成本相关。该项目的长期目标是协助新型非抗生素药物的开发和临床应用，以预防和治疗艰难梭菌相关的腹泻和结肠炎。该提议的中心假设是宿主因素，尤其是对艰难梭菌抗原的免疫反应，在确定艰难梭菌感染的临床结果中发挥着重要作用。我们将对 150 名艰难梭菌相关性腹泻 (CDAD) 受试者进行一项前瞻性队列研究，以检验以下三个假设： 假设 1：对艰难梭菌毒素 A 和毒素 B 的免疫反应有助于预防复发CDAD。我们最近的研究表明，在预防症状性或复发性 CDAD 的受试者中，对艰难梭菌毒素 A 的血清 IgG 反应很明显。为此，我们将确定对毒素 B 的体液和细胞介导的免疫反应、对毒素 A 重组肽的免疫反应和/或毒素中和活性是否也与保护相关。假设 2：可以根据临床参数和/或抗毒素抗体测量来预测 CDAD 复发的风险。根据我们之前对 CDAD 患者（衍生队列）的研究，我们制定了预测复发的准确率 >80% 的预测规则。为此，我们将在为特定目标 1（验证队列）招募的 150 名受试者中前瞻性地测试这些规则。一旦经过验证，这些工具可用于临床实践和研究中，以确定最有可能从预防复发性艰难梭菌感染的措施中受益的高风险患者。假设 3：对艰难梭菌表面层蛋白 (SLP) 的免疫反应可以防止定植和/或 CDAD。先前对艰难梭菌免疫反应的研究几乎完全集中在抗毒素抗体上。艰难梭菌表面层蛋白 (SLP) 是艰难梭菌中的主要表面蛋白，最近在分子水平上得到了表征，并且似乎充当细菌粘附素。我们的初步数据表明，对艰难梭菌表面层蛋白的免疫反应可能具有保护性。在此目的中，我们将比较单次 CDAD 受试者、患有复发性疾病的受试者以及疾病和健康对照受试者对纯化和重组艰难梭菌 SLP 的体液和细胞介导的免疫反应。我们还将确定针对艰难梭菌 SLP 的疫苗接种是否可以预防仓鼠中艰难梭菌定植和/或艰难梭菌相关的回肠盲肠炎。这些具体目标旨在进一步增进我们对艰难梭菌毒素引起的腹泻的免疫生物学和人类免疫保护机制的了解。