IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM

描述：(改编自申请人摘要)微小隐孢子虫 免疫功能低下患者的感染通常发展为慢性、严重的 可能危及生命的隐孢子虫病。与LOW一起使用 CD4细胞水平，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。关于免疫学的阐明 免疫失调的反应和特征的识别，如 细胞因子异常或T细胞无法增殖以应对 关键的隐孢子虫抗原，可能会识别高危或 隐孢子虫病。据推测，感染的解决方案 具有免疫活性的宿主与特定的抗原相连，负责 淋巴细胞群的激活和细胞因子的诱导。因此， 对这些关键抗原缺乏反应和某些细胞因子的发展 个人资料可能会导致慢性、难治性感染。这个项目的总体目标是 建议识别在免疫中重要的隐孢子虫抗原 应对和恢复。这些抗原可能是抗体的靶标，从而阻断 侵袭性寄生虫期的附着和穿透，阻断受精 性阶段或可能是细胞免疫(CMI)反应的目标。 来自cDNA文库的重组抗原，通过它们对 特定的抗隐孢子虫抗体和自然抗原部分将 用作抗原的来源。申请者将确定 通过评估这些抗原诱导细胞免疫的能力 使用鼠标模型进行响应。由于粘膜T细胞被认为扮演着 在对这种寄生虫的免疫中起着关键作用，这些抗原也将 评估它们在体外诱导T细胞反应的能力 起源于固有层和肠系膜淋巴结，以及来自 雅思。研究人员将评估在体内产生的各种细胞因子 在小鼠细胞群体中对这些抗原的反应。此外，T细胞 将建立并嫁接针对这些关键抗原中的3-4个的克隆 变成受感染的小鼠。这些细胞系的能力将降低或清除 感染将有助于确定这些抗原是否在反应中起重要作用 在康复过程中。成功使用预防和治疗方法 需要对自然免疫机制有更好的了解 为了控制感染。

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.