Site specific targeting of cellular immune responses

描述（由申请人提供）：先天性免疫应答的抗原呈递细胞（APC）与适应性免疫应答的T淋巴细胞一起产生细胞免疫。APC将病原体/肿瘤抗原加工成10-20个氨基酸的肽，同时它们运输到最近的引流结的位点。在淋巴结处，APC沿着额外的激活信号将“加工的”抗原肽呈递给T淋巴细胞。一旦激活，T淋巴细胞离开淋巴结并返回到病原体/肿瘤部位，在那里它们攻击表达这些抗原肽的细胞。T细胞定位于病原体/肿瘤的部位，这是由于产生对特定部位（例如肠道和皮肤）特异性的APC衍生因子。本研究的一个主要目标是将肿瘤特异性T细胞引导至特定部位，并提供可以产生抗原和部位特异性T细胞免疫的概念证明。具体目标：目的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CCR 9和CCR 10 T细胞的频率和/或功能是否与免疫途径相关。目的2将确定T细胞的频率和/或功能是否可以通过适当修改免疫疗法而独立于免疫途径受到影响。目标3将确定T细胞的这种频率和/或功能是否可以独立于途径受到影响，即使当引流淋巴结功能障碍或缺失时。为了解决特定的目标，免疫疗法将被工程化，含有抗原的整个酵母，也产生对T细胞归巢重要的激素-维生素D（皮肤归巢）或维生素A（肠道归巢）。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接种将确定抗原特异性T细胞的频率是否会受到与抗原注射位置相反的影响。这些实验可以在皮肤处“印记”呈递有抗原的T细胞，以替代地进入肠道，或者相反地在肠道中印记呈递有抗原的T细胞，以进入皮肤。虽然这些印迹实验已经通过体外培养T细胞、DC和维生素进行，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细胞归巢的手段。 公共卫生相关性：其目标是帮助免疫系统首先识别肿瘤是外来的并攻击它，其次帮助免疫系统识别肿瘤的位置并将大部分免疫反应导向肿瘤。虽然目前只知道肠道和皮肤特异性免疫应答因子，但可以合理地假设将发现其他器官特异性因子。考虑到这一点，我们将设计癌症免疫疗法到任何位置，并帮助肿瘤消退，无论位置如何。

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.