IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM

描述：（改编自申请人的摘要）隐孢子虫 免疫功能低下个体的感染通常发展成慢性、严重的 隐孢子虫病会危及生命与低 CD 4+细胞水平，其他免疫系统因素预计有助于 免疫缺陷宿主的感染慢性化。阐明免疫 反应和识别免疫失调的特征，如 细胞因子异常或T细胞不能响应于 关键的隐孢子虫抗原，可以识别高风险的患者， 隐孢子虫病据推测，感染的解决， 免疫活性宿主与负责免疫应答的特异性抗原连接。 淋巴细胞群的活化和细胞因子的诱导。因此，委员会认为， 缺乏对这些关键抗原的反应和某些细胞因子的产生 可能导致慢性、难治性感染。这个项目的总体目标是 建议是鉴定在免疫中重要的隐孢子虫抗原， 响应和恢复。这些抗原可能是阻断免疫应答的抗体的靶标。 入侵寄生虫的附着和渗透阶段， 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，通过其与以下抗原的反应性鉴定： 特异性抗隐孢子虫抗体和天然抗原部分将 用作抗原来源。申请人将确定以下内容的重要性： 通过评估这些抗原中的每一种引起细胞免疫的能力， 使用小鼠模型的反应。由于粘膜T细胞被认为是发挥作用， 在对这种寄生虫的免疫中起着关键作用，这些抗原也将 评价它们在体外诱导T细胞应答的能力 起源于固有层和肠系膜淋巴结以及来自 IELs。研究人员将评估在这些细胞中产生的各种细胞因子。 在鼠细胞群体中对这些抗原的应答。此外，T细胞 将建立并移植对这些关键抗原中的3-4种特异的克隆 感染的老鼠。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在应答中是否重要 在恢复中。成功使用预防和治疗方法 需要更好地理解自然免疫机制 来控制感染

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.