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Resident Memory T cells in Leishmaniasis

利什曼病中的常驻记忆 T 细胞

基本信息

批准号：
9916704
负责人：
PHILLIP SCOTT
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-16 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916704
关键词：
Adjuvant Adoptive Transfer Antigens CD4 Positive T Lymphocytes Cell Differentiation process Cells Cellular Immunity Cutaneous Development Disease Eragrostis Future Generations Genus Mycobacterium Goals Human Immunity Immunization Infection Inflammatory Interferon Type II Interferons Leishmania Leishmania major Leishmaniasis Lesion Link Mediating Memory Methods Mus Nature Parasite Control Parasites Plasmodium Primary Infection Proteins Resistance Resolution Role Route Seeds Skin Skin graft Source T cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Toxoplasma Translating Vaccination Vaccines Vaccinia Vaccinia virus cell motility design effector T cell migration monocyte neglected tropical diseases pathogen pathogenic microbe recruit response success tool vaccine development vaccine efficacy vaccine evaluation vaccine-induced immunity

项目摘要

The development of effective vaccines for intracellular microbial pathogens, such as mycobacteria, toxoplasma, plasmodium, and leishmania, remains an elusive goal. Despite substantial efforts to define the mechanisms required for resistance, develop new adjuvants, and identify protective antigens, the long-lived cellular immunity that can be generated in response to infection is not always recapitulated by vaccination. For example, in spite of the strong immunity that develops following an infection with leishmania, efforts to develop a vaccine for human leishmaniasis have been unsuccessful. Lack of success is due in part to the limited understanding of the T cells that mediate protection. While we have identified circulating T cell subsets that contribute to immunity in leishmaniasis (1), these circulating T cells fail to provide the level of immunity observed in mice that have resolved a primary infection with L. major. Using a combination of skin grafting and adoptive transfers, however, we found that leishmania-responsive IFN-γ producing CD4+ T cells resident in the skin are the missing link required for optimal protective immunity (2). We propose to identify how they are generated and maintained in the skin, determine how they promote immunity, and target them in a leishmanial vaccine. These studies are important for leishmaniasis, and have broad implications for vaccine development against other pathogens. In Aim 1 we will define the factors that regulate the accumulation of CD4+ resident memory T cells in the skin following resolution of a primary infection. These studies have direct relevance to vaccine development, as they will define what will be required for generating resident memory T cells. In Aim 2, we focus on the mechanisms by which resident memory T cells mediate protection. Here we will identify the effector T cells that synergize with resident memory T cells to mediate protection, and determine if resident memory T cells help to amplify the generation of T effector cells. Finally, in Aim 3 we will translate this information into an experimental vaccine. We will create a recombinant vaccinia virus expressing a leishmanial antigen, and assess the protection induced by this vaccine and qualitatively and quantitatively define the T cells that contribute to that protection.

开发针对细胞内微生物病原体（例如分枝杆菌）的有效疫苗弓形虫、疟原虫和利什曼原虫仍然是一个难以捉摸的目标。尽管做出了巨大努力来定义耐药所需的机制，开发新的佐剂，并识别保护性抗原，即长寿命的因感染而产生的细胞免疫并不总是通过疫苗接种来重现。例如，尽管感染利什曼原虫后会产生很强的免疫力，但仍需努力开发人类利什曼病疫苗尚未成功。未能取得成功的部分原因是对介导保护作用的 T 细胞的了解有限。虽然我们已经鉴定出循环 T 细胞有助于利什曼病免疫的亚群 (1)，这些循环 T 细胞无法提供以下水平在已经解决了重大利斯特氏菌原发感染的小鼠中观察到的免疫力。使用混合皮肤然而，我们发现利什曼原虫反应性 IFN-γ 产生 CD4+ T 皮肤中的细胞是最佳保护性免疫所需的缺失环节 (2)。我们建议确定它们如何在皮肤中产生和维持，确定它们如何促进免疫力，以及以利什曼病疫苗为目标。这些研究对于利什曼病很重要，并且具有广泛的意义对针对其他病原体的疫苗开发的影响。在目标 1 中，我们将定义以下因素：调节原发性皮肤病消退后 CD4+ 常驻记忆 T 细胞的积累感染。这些研究与疫苗开发直接相关，因为它们将定义什么是疫苗生成常驻记忆 T 细胞所需的。在目标 2 中，我们重点关注居民的机制记忆 T 细胞介导保护。在这里，我们将鉴定与常驻细胞协同作用的效应 T 细胞记忆 T 细胞介导保护，并确定常驻记忆 T 细胞是否有助于放大效应T细胞的产生。最后，在目标 3 中，我们将把这些信息转化为实验结果疫苗。我们将创建表达利什曼原虫抗原的重组痘苗病毒，并评估该疫苗诱导的保护作用，并定性和定量地定义了有助于保护的 T 细胞那种保护。