IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM

CMI 对隐孢子虫的免疫显性靶点

• 批准号: 6373417
• 负责人: JAN R MEAD
• 金额: $ 19.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373417
• 关键词: Cryptosporidium; T lymphocyte; cell population study; cellular immunity; cryptosporidiosis; cytokine; genetic library; helper T lymphocyte; immunodeficiency; laboratory mouse; lymphocyte proliferation; microorganism immunology; mucosal immunity; passive immunization; protozoal antigen; recombinant proteins; tissue /cell culture; western blottings

DESCRIPTION: (Adapted from Applicant's Abstract) Cryptosporidium parvum infections in immunocompromised individuals often develop into chronic, severe cryptosporidiosis that can become life-threatening. In conjunction with low CD4+ cell levels, other immune system factors are expected to contribute to infection chronicity in the immunodeficient host. Elucidation of immune responses and identification of features of immune dysregulation, such as cytokine abnormalities or inability of T-cells to proliferate in response to key cryptosporidial antigens, might identify patients at high risk or cryptosporidiosis. It is hypothesized that infection resolution in the immunocompetent host is linked to specific antigens responsible for the activation of lymphocyte populations and induction of cytokines. Consequently, a lack of response to these key antigens and development of certain cytokine profiles may lead to chronic, intractable infections. The overall goal of this proposal is to identify cryptosporidial antigens that are important in immune response and recovery. These antigens may be targets of antibody that block the attachment and penetration of invasive parasite stages, block fertilization in the sexual stages or may be targets of cell-mediated immune (CMI) responses. Recombinant antigens from a cDNA library, identified by their reactivity to specific anti-cryptosporidial antibodies and native antigen fractions will be used as the source of antigen. The applicants will establish the importance of each of these antigens by assessing their ability to elicit cellular immune responses using a mouse model. Since mucosal T-cells are thought to play a critical role in the immunity to this parasite, these antigens will also be evaluated for their ability to elicit in vitro responses from T-cells originating in the lamina propria and mesenteric lymph nodes as well as from IELs. The investigators will evaluate the various cytokines produced in response to these antigens in murine cell populations. Additionally, T-cell clones specific for 3-4 of these key antigens will be established and engrafted into infected mice. The ability of these cell lines will to reduce or clear infection will aid in determining if these antigens are important in response and in recovery. Successful use of prophylactic and treatment modalities requires an improved understanding of the natural immune mechanisms responsible for the control of the infection.

描述：（改编自申请人的摘要）小隐孢子虫 免疫功能低下个体的感染常常发展为慢性、严重的 可能危及生命的隐孢子虫病。与低 CD4+ 细胞水平以及其他免疫系统因素预计将有助于 免疫缺陷宿主的慢性感染。免疫的阐明 反应和免疫失调特征的识别，例如 细胞因子异常或 T 细胞无法响应增殖 关键的隐孢子虫抗原，可能会识别高危患者或 隐孢子虫病。据推测，感染解决 具有免疫活性的宿主与负责免疫的特定抗原相关 淋巴细胞群的激活和细胞因子的诱导。最后， 对这些关键抗原缺乏反应以及某些细胞因子的发育 情况可能会导致慢性、难治性感染。本次活动的总体目标 提议是鉴定对免疫很重要的隐孢子虫抗原 反应和恢复。这些抗原可能是抗体的靶标，可阻断 侵入性寄生虫阶段的附着和渗透，阻止受精 性阶段或可能是细胞介导的免疫（CMI）反应的目标。 来自 cDNA 文库的重组抗原，通过其与 特异性抗隐孢子虫抗体和天然抗原组分将 用作抗原的来源。申请人将确定以下事项的重要性： 通过评估每种抗原引发细胞免疫的能力 使用小鼠模型做出反应。由于粘膜 T 细胞被认为发挥着 这些抗原在对该寄生虫的免疫中发挥着关键作用，也将被 评估其引发 T 细胞体外反应的能力 起源于固有层和肠系膜淋巴结以及 IEL。研究人员将评估产生的各种细胞因子 小鼠细胞群对这些抗原的反应。此外，T细胞 将建立并移植对其中 3-4 种关键抗原具有特异性的克隆 进入受感染的小鼠体内。这些细胞系的能力将减少或清除 感染将有助于确定这些抗原是否对反应很重要 并在康复中。成功使用预防和治疗方法 需要更好地了解负责的自然免疫机制 以控制感染。