Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis

CD8 T 细胞在利什曼病中的保护和病理作用

基本信息

批准号：
9300849
负责人：
PHILLIP SCOTT
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-21 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300849
关键词：
Alpha Cell Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Characteristics Cutaneous Cutaneous Leishmaniasis Cytolysis Data Development Disease Disease Progression Down-Regulation Effector Cell Environment Foundations Future Goals Granzyme Human Immune Immune response Immunity Immunotherapy Infection Inflammation Inflammatory Response Interferons Interleukin-10 Interleukin-12 Interleukin-15 Intrinsic factor Leishmania Leishmaniasis Lesion Ligands Link Lymphocyte Count Lymphocytic choriomeningitis virus Mediating Memory Modeling Mus Neoplasm Metastasis Parasites Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Play Primary Infection Production Recruitment Activity Resolution Role Severity of illness Signal Transduction Site Specificity T cell differentiation T-Lymphocyte Testing Therapeutic Tissues Transcription Repressor/Corepressor Translating Up-Regulation cell killing cytokine cytotoxic design experimental study immunopathology inflammatory milieu interleukin-12 receptor killings lymph nodes macrophage neglected tropical diseases novel novel therapeutic intervention novel therapeutics pathogen perforin public health relevance receptor receptor expression response secondary infection skin lesion

Alpha Cell Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Characteristics Cutaneous Cutaneous Leishmaniasis Cytolysis Data Development Disease Disease Progression Down-Regulation Effector Cell Environment Foundations Future Goals Granzyme Human Immune Immune response Immunity Immunotherapy Infection Inflammation Inflammatory Response Interferons Interleukin-10 Interleukin-12 Interleukin-15 Intrinsic factor Leishmania Leishmaniasis Lesion Ligands Link Lymphocyte Count Lymphocytic choriomeningitis virus Mediating Memory Modeling Mus Neoplasm Metastasis Parasites Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Play Primary Infection Production Recruitment Activity Resolution Role Severity of illness Signal Transduction Site Specificity T cell differentiation T-Lymphocyte Testing Therapeutic Tissues Transcription Repressor/Corepressor Translating Up-Regulation cell killing cytokine cytotoxic design experimental study immunopathology inflammatory milieu interleukin-12 receptor killings lymph nodes macrophage neglected tropical diseases novel novel therapeutic intervention novel therapeutics pathogen perforin public health relevance receptor receptor expression response secondary infection skin lesion

展开

项目摘要

DESCRIPTION (provided by applicant): Leishmaniasis is an important neglected tropical disease that occurs worldwide, and is caused by several different parasites with different characteristics. L. braziliensis infections are particularly distinct from other forms of leishmaniasis, since disease severity is not due to uncontrolled parasite replication, but rather t an exaggerated immune response. Thus, therapeutics designed to increase parasite killing are detrimental if they concomitantly enhance inflammatory responses. Our new data strongly suggests that optimal control of L. braziliensis requires a response that not only effectively eliminates the parasite, but also reduces the potential for immunopathology. We have made two unexpected observations demonstrating that CD8 T cells contribute to leishmanial immunopathology. First, we find that unregulated CD8 T cells mediate severe perforin-dependent pathology, which is associated with CD8 T cell killing of infected cells. Furthermore, we also find that CD8 T cells promote increased metastasis of the parasites, which provides a model to investigate the factors contributing to the development of metastatic lesions in patients. Second, we find that mice that have resolved an infection with lymphocytic choriomeningitis virus (LCMV) maintain an expanded CD8 pool and, when challenged with Leishmania, recruit large numbers of LCMV specific CD8 T cells to the lesions, with an associated increase in disease severity. In contrast to Leishmania-specific CD8 T cells that can kill Leishmania infected target cells, we hypothesize that these LCMV specific CD8 T cells (or bystander T cells) promote increased inflammation either due to non-specific lysis of target cells via an activating receptor known as NKG2D, or due to cytokine-induced release of granzyme B (GrzB). These findings suggest that control of the pathogenic activity of CD8 T cells might be a good approach for developing new immunotherapies for cutaneous leishmaniasis. We propose three specific aims to advance our understanding of the disease and provide a foundation for new therapeutic approaches. In Aim 1 we will evaluate how the lesion environment influences CD8 function. We find that CD8 T cell function is determined by the cytokine milieu and we propose experiments to determine if pathogenic CD8 T cells can be converted to protective cells. In Aim 2, we focus on defining how the bystander CD8 T cells promote increased disease, particularly focusing on the role of NKG2D and GzmB. Finally, in Aim 3 we will determine how CD8 T cells become protective following resolution of a primary infection. Taken together, these studies will provide new information about this disease that can be translated into new therapies.

描述（由申请人提供）：利什曼病是一种重要的被忽视的热带疾病，它在全球范围内发生，是由几种具有不同特征的不同寄生虫引起的。巴西乳杆菌感染与其他形式的利什曼病特别不同，因为疾病的严重程度不是由于不受控制的寄生虫复制引起的，而是夸张的免疫反应。因此，如果旨在增加寄生虫杀死的治疗剂同时增强炎症反应，则它们是有害的。我们的新数据强烈表明，对巴西乳杆菌的最佳控制需要一种反应，不仅有效地消除了寄生虫，而且还降低了免疫病理学的潜力。我们进行了两个意外的观察结果，表明CD8 T细胞有助于利什人类免疫病理学。首先，我们发现不受管制的CD8 T细胞介导严重的穿孔依赖性病理，这与受感染细胞的CD8 T细胞杀死有关。此外，我们还发现CD8 T细胞促进了寄生虫的转移增加，该模型提供了研究导致患者转移性病变发展的因素。其次，我们发现已经解决了用淋巴细胞绒毛膜炎病毒（LCMV）解决感染的小鼠保持扩大的CD8池，并且在利什曼尼亚挑战时，将大量的LCMV特异性CD8 T细胞募集到病变中，并在疾病严重程度上增加了相关的疾病严重增加。与可以杀死利什曼原虫感染靶细胞的利什曼原虫特异性CD8 T细胞相反，我们假设这些LCMV特异性CD8 T细胞（或旁观者T细胞）促进了炎症增加了炎症，这是由于靶细胞通过称为NKG2D的激活受体而引起的靶细胞引起的，或者是由于细胞油诱导的granzyme granzyme的释放（granzyb）。这些发现表明，控制CD8 T细胞的致病活性可能是为皮肤利什曼病开发新的免疫疗法的良好方法。我们提出了三个特定的目标，以提高我们对疾病的理解，并为新的治疗方法提供基础。在AIM 1中，我们将评估病变环境如何影响CD8功能。我们发现CD8 T细胞功能由细胞因子环境确定，我们提出实验以确定是否可以将病原性CD8 T细胞转化为保护细胞。在AIM 2中，我们专注于定义旁观者CD8 T细胞如何促进疾病，特别是专注于NKG2D和GZMB的作用。最后，在AIM 3中，我们将确定CD8 T细胞在分辨原发性感染后如何保护性。综上所述，这些研究将提供有关该疾病的新信息，这些信息可以转化为新疗法。