Site specific targeting of cellular immune responses

细胞免疫反应的位点特异性靶向

• 批准号: 7546438
• 负责人: Beth Ann Tamburini
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546438
• 关键词: Address; Amino Acids; Antigen-Presenting Cells; Antigens; CCR9 gene; Cells; Cellular Immunity; Data; Disease regression; Engineering; Frequencies; GPR2 gene; Goals; Homing; Hormones; Immune response; Immune system; Immunity; Immunization; Immunotherapeutic agent; Immunotherapy; In Vitro; Left; Localized; Location; Lymphatic; Lymphoid Tissue; Mind; Organ; Peptides; Process; Production; Public Health; Route; Signal Transduction; Site; Skin; T-Lymphocyte; Tumor Antigens; Ursidae Family; Vitamin A; Vitamin D; Vitamins; Work; Yeasts; base; cancer immunotherapy; cellular targeting; chemokine receptor; concept; imprint; in vivo; lymph nodes; novel; pathogen; research study; tumor

DESCRIPTION (provided by applicant): Antigen presenting cells (APC)s of the innate immune response work together with T lymphocytes of the adaptive immune response to generate cellular immunity. APCs process the pathogen/tumor antigens into peptides of 10-20 amino acids while they are in transit to the site of the nearest draining node. At the node, the "processed" antigenic peptides are presented to T lymphocytes by the APCs along with additional activating signals. Once activated, T lymphocytes leave the node and return to the site of pathogen/tumor where they attack cells that express these antigenic peptides. T cells localize to the site of the pathogen/tumor due to the production of APC-derived factors specific to particular sites such as gut and skin. A major goal of this study is to direct tumor specific T cells to a particular site and to provide proof of concept that both antigen and site specific T cell immunity can be produced. Specific aims: Aim 1 will use yeast based immunotherapy approach to determine if the frequency and/or function of CCR9 and CCR10 T cells in various lymphoid tissues correlates with the route of immunization. Aim 2 will determine if frequency and/or function of T cells can be influenced independent of the route of immunization by appropriately modifying the immunotherapy. Aim 3 will determine if this frequency and/or function of T cells can be influenced independent of route even when the draining lymph nodes are dysfunctional or absent. To address the specific aims immunotherapy will be engineered, whole yeast containing antigen, to also produce hormones important for T cell homing - either Vitamin D (skin homing) or Vitamin A (gut homing). Immunization with the immunotherapy containing Vitamin A in the skin and/or Vitamin D in the gut will determine if frequency of antigen specific T cells can be influenced counter to where the antigen was injected. These experiments may "imprint" T cells presented with antigen at the skin to alternatively go to gut, or conversely imprint T cells presented with antigen in the gut to go to skin. While these imprinting experiments have been performed by culturing T cells, DCs and vitamins in vitro this would be a means to avoid these complicated manipulations and induce antigen specific T cell homing entirely in vivo. PUBLIC HEALTH RELEVANCE: The goal is to help the immune system first recognize a tumor as foreign and attack it and second to help the immune system recognize the location of the tumor and direct the bulk of the immune response to the tumor. While currently only gut and skin specific immune response factors are known it is reasonable to assume that other organ specific factors will be discovered. With this in mind we will engineer cancer immunotherapy to any location and aid in tumor regression regardless of location.

描述（由申请人提供）：先天性免疫反应的抗原呈递细胞（APC）与适应性免疫反应的T淋巴细胞一起工作以产生细胞免疫。当病原体/肿瘤抗原运送到最近的引流节点时，APC 将它们加工成 10-20 个氨基酸的肽。在节点，“加工过的”抗原肽与其他激活信号一起由 APC 呈递给 T 淋巴细胞。一旦被激活，T淋巴细胞就会离开淋巴结并返回病原体/肿瘤部位，在那里它们攻击表达这些抗原肽的细胞。由于产生特定于肠道和皮肤等特定部位的 APC 衍生因子，T 细胞定位于病原体/肿瘤部位。这项研究的一个主要目标是将肿瘤特异性 T 细胞引导至特定位点，并提供可以产生抗原和位点特异性 T 细胞免疫的概念证明。具体目标：目标 1 将使用基于酵母的免疫治疗方法来确定各种淋巴组织中 CCR9 和 CCR10 T 细胞的频率和/或功能是否与免疫途径相关。目标 2 将确定是否可以通过适当修改免疫疗法来独立于免疫途径影响 T 细胞的频率和/或功能。目标 3 将确定即使引流淋巴结功能失调或缺失，T 细胞的频率和/或功能是否会受到独立于途径的影响。为了实现特定目标，免疫疗法将被设计为含有抗原的完整酵母，以产生对 T 细胞归巢很重要的激素 - 维生素 D（皮肤归巢）或维生素 A（肠道归巢）。使用皮肤中含有维生素 A 和/或肠道中含有维生素 D 的免疫疗法进行免疫将确定抗原特异性 T 细胞的频率是否会受到注射抗原位置的影响。这些实验可能会在皮肤上“印记”呈递抗原的 T 细胞，以选择性地进入肠道，或者相反，在肠道中印记呈递抗原的 T 细胞以进入皮肤。虽然这些印记实验是通过在体外培养 T 细胞、DC 和维生素来进行的，但这将是避免这些复杂操作并完全在体内诱导抗原特异性 T 细胞归巢的一种方法。 公共健康相关性：目标是首先帮助免疫系统将肿瘤识别为外来物并对其进行攻击，其次帮助免疫系统识别肿瘤的位置并将大部分免疫反应引导至肿瘤。虽然目前仅已知肠道和皮肤特异性免疫反应因子，但可以合理地假设将会发现其他器官特异性因子。考虑到这一点，我们将针对任何位置设计癌症免疫疗法，并帮助肿瘤消退，无论位置如何。