L. Brazilensis Vaccine Antigens and T-cell Quality in Protection

巴西乳杆菌疫苗抗原和保护中的 T 细胞质量

基本信息

批准号：
8430973
负责人：
LYNN SOONG
金额：
$ 7.73万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430973
关键词：
Adjuvant American Leishmaniasis Animal Model Antigens Area Bacteria Bioinformatics Biological Assay CD4 Positive T Lymphocytes Cells Chronic Disease Clinical Complex Cutaneous Leishmaniasis DNA Diffuse Cutaneous Leishmaniasis Disease Epitopes Evaluation Evolution Failure Frequencies Genomics Goals Human Immune response Immunity Immunization In Vitro Infection Interferons Interleukin-2 Knowledge Leishmania Leishmaniasis Life Lipid A Memory Modeling Molecular Mouse Strains Mucocutaneous leishmaniasis Mus Nature Parasites Pathogenesis Pharmaceutical Preparations Proteins Prunella vulgaris Public Health Regimen Regulation South America Staging System T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes TLR4 gene TNF gene Testing Travel Tropical Disease Vaccination Vaccine Antigen Vaccine Design Vaccines Virus antigen L base chemotherapy cytokine design empowered immunogenicity improved in vivo innovation monophosphoryl lipid A neglect novel pathogen programs public health relevance response skin lesion tool vaccine candidate vaccine development vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): Leishmaniasis encompasses a broad spectrum of neglected, but important tropical diseases; yet there are no effective vaccines for any clinical forms of the disease. The major obstacle in developing an effective anti- Leishmania vaccine is insufficient information on parasite antigens that elicit protective T-cell responses and appropriate regulation, since inadequate and excessive immune responses can contribute to pathogenesis, leading to vaccine failure. Our studies in animal models have revealed detrimental and protective immune responses programmed at the initial stages of infections with L. amazonensis and L. braziliensis, respectively. We hypothesized that vaccination with rationally selected T-cell antigens of L. braziliensis, together with appropriate adjuvants, can elicit a broad-spectrum and high-quality T-cell immunity for the control of American cutaneous leishmaniasis. This hypothesis will be tested in two Specific Aims. Aim 1 will examine whether L. braziliensis candidates identified through an immunoinformatics approach can cross-protect mice against another New World Leishmania spp infection. The immunogenicity and vaccine potential of the top three candidates will be tested via DNA- and protein-based immunization regimens, in conjunction with novel TLR4- adjuvants glucopyranosyl lipid A (GLA) and monophosphoryl lipid A (MPL). Aim 2 will test the hypothesis that the level of protection offered by various vaccines positively correlates with the quality and spectrum of T-cell responses. In vitro and in vivo assays will be used to analyze the frequency of multi-functional CD4+ T effector and memory cells during immunization and parasite challenge. We will examine the molecular basis of protection induced by vaccine immunization and chemotherapy. The long-term goal of this study is to define the protective mechanisms associated with Leishmania infection and to utilize this information for the design of control strategies for this and other persistent parasitc infections. The innovation of this study is our comprehensive approaches for identifying new T-cell antigens of L. braziliensis and evaluating T-cell quality and cross-species protection. This study is highly relevant to the rational vaccine design for non-healing leishmaniasis, but also has broad implications for other chronic diseases caused by intracellular pathogens.

描述（由申请人提供）：利什曼病涵盖了广泛的被忽视但重要的热带疾病；然而，对于任何临床形式的疾病都没有有效的疫苗。开发有效的抗利什曼原虫疫苗的主要障碍是关于寄生虫抗原的信息不足，因为寄生虫抗原会引起保护性T细胞反应和适当的调节，因为不足和过度的免疫反应会导致病原体，从而导致疫苗失败。我们在动物模型中的研究揭示了分别在亚马逊乳杆菌和巴西乳杆菌的初始阶段进行了有害和保护性免疫反应。我们假设，巴西乳杆菌的合理选择的T细胞抗原以及适当的佐剂可以引起广谱和高质量的T细胞免疫，以控制美国皮肤利什曼病。该假设将以两个具体的目的进行检验。 AIM 1将检查通过免疫信息学方法确定的巴西候选者是否可以与另一个新世界利什曼尼亚SPP感染交叉保护小鼠。前三名候选物的免疫原性和疫苗电位将通过基于DNA和蛋白质的免疫治疗方案进行测试，并与新型TLR4-辅助葡萄糖基脂质脂质A（GLA）和单磷酸脂质脂质A（MPL）结合使用。 AIM 2将检验以下假设：各种疫苗提供的保护水平与T细胞反应的质量和光谱呈正相关。体外和体内测定将用于分析免疫和寄生虫挑战期间多功能CD4+ T效应细胞和记忆细胞的频率。我们将检查疫苗免疫和化学疗法引起的保护的分子基础。这项研究的长期目标是定义与利什曼原虫感染相关的保护机制，并利用此信息来设计该控制策略和其他持久性寄生虫感染。这项研究的创新是我们识别巴西乳杆菌的新T细胞抗原并评估T细胞质量和跨物种保护的全面方法。这项研究与非治疗利什曼病的理性疫苗设计高度相关，但也有对由细胞内病原体引起的其他慢性疾病的广泛影响。