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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.

针对细胞内微生物病原体如分枝杆菌的有效疫苗的开发，弓形虫、疟原虫和利什曼原虫，仍然是一个难以捉摸的目标。尽管作出了大量努力，耐药所需的机制，开发新的佐剂，并确定保护性抗原，可响应感染而产生的细胞免疫并不总是通过疫苗接种重现。例如，尽管在感染利什曼原虫后产生了强免疫力，但仍努力但是，人类利什曼病疫苗的开发一直不成功。缺乏成功的部分原因是对介导保护作用的T细胞的了解有限。虽然我们已经确定了循环T细胞在利什曼病（1）中有助于免疫的亚群，这些循环T细胞不能提供在已经解决了L.少校使用皮肤和然而，我们发现利什曼病应答性IFN-γ产生的CD 4 + T细胞驻留在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，用利什曼原虫疫苗来对付他们这些研究对利什曼病很重要，对其他病原体疫苗开发的影响。在目标1中，我们将定义调节CD 4+驻留记忆T细胞在皮肤中的积累，感染这些研究与疫苗开发直接相关，因为它们将确定这是产生常驻记忆T细胞所必需的。在目标2中，我们关注的是居民记忆T细胞介导保护作用。在这里，我们将确定与常驻T细胞协同作用的效应T细胞。记忆T细胞介导的保护，并确定是否驻留记忆T细胞有助于放大 T效应细胞的产生。最后，在目标3中，我们将把这些信息转化为实验性的疫苗我们将创建一个表达利什曼原虫抗原的重组牛痘病毒，并评估其对利什曼原虫感染的影响。保护诱导这种疫苗和定性和定量定义T细胞，有助于这种保护。