Self-assembling Peptide Nanomaterials for Eliciting Mucosal CD8+ T cell Immunity

用于引发粘膜 CD8 T 细胞免疫的自组装肽纳米材料

基本信息

批准号：
9036015
负责人：
Janice J Endsley
金额：
$ 22.76万
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：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036015
关键词：
Adjuvant Adolescence Adult Aerosols Agonist Air Alveolar Cell Alveolar Macrophages Antibody Response Area Attenuated Bacterial Toxins Breathing CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Immunity Cessation of life Cholera Toxin Clinical Containment Development Dose Epitopes Escherichia coli Formulation Foundations Health Host Defense Human Immune response Immunity Immunization Immunocompromised Host Immunologic Adjuvants Immunologist Immunology Individual Infection Injection of therapeutic agent Interferon Type II Interleukin-2 Intramuscular Invaded Life Link Liver Lung Lymphoid Tissue Memory Modeling Mucosal Immunity Mucous Membrane Mus Mycobacterium tuberculosis Nanotechnology Needles Organ Peptides Peripheral Play Population Prophylactic treatment Public Health Research Respiratory Mucosa Risk Role Route Safety Scientist Self Efficacy Site Subunit Vaccines Surface Synthesis Chemistry T cell response T memory cell T-Lymphocyte T-Lymphocyte Epitopes TNF gene Tertiary Protein Structure Testing Tissues Toll-like receptors Toxic effect Tuberculosis Vaccinated Vaccines Work active control aerosolized aluminum sulfate base combat enterotoxin LT global health immunogenic immunogenicity improved influenzavirus interest killings lymph nodes mucosal site mucosal vaccine nanofiber nanomaterials neutralizing antibody pathogen peripheral blood precursor cell public health relevance respiratory response vaccination strategy vaccine development vector vaccine

项目摘要

DESCRIPTION (provided by applicant): Immunization strategies that elicit robust memory CD8+T cell responses in mucosal tissues are important to facilitate early containment of nascent infections, as it is estimated that 70% of pathogens initiate infection via mucosal surfaces. While neutralizing antibody responses are clinical correlates of protection, tissue-resident memory CD8+T cells have been shown to protect against infections by immediately recognizing and killing infected cells. Therefore mucosal immunization strategies capable of eliciting robust memory CD8+T cell populations in target mucosal tissue are of great interest. However, a major limiting factor to the development of successful mucosal vaccines is the lack of effective and safe immune adjuvants. In the current project, we will develop and investigate the efficacy of self-assembling peptide nanomaterials for eliciting protective mucosal CD8+T cell responses Mycobacterium tuberculosis (Mtb), which is a major global health burden. We will utilize peptide nanofibers constructed from self-assembling peptides linked to antigenic epitopes from Mycobacterium tuberculosis (Mtb) and investigate effector and memory CD8+T cell responses after intranasal immunization in mice. In aim 1, we will synthesize peptide nanofibers bearing native CD8+T cell epitopes alone or co-assembled with Mtb-specific CD4+T helper epitopes to elicit robust cellular immunity in the lung. Formulations with a strong immunogenicity profile will be tested for protection against infection using an aerosolized Mtb challenge to mimic natural route of Mtb infection. Bacterial load in the lung, liver, and other organs will be determined to assess protection. In Aim 2, we will incorporate synthetic toll-like receptor (TLR) agonists into protective peptide nanofiber vaccine formulations from Aim 1 to expand memory CD8+T cell populations with multifunctional recall activity. Mucosal and systemic effector and memory responses will be determined after intranasal delivery of nanofiber vaccines and enhanced protection will be assessed using an aerosolized Mtb model. Completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and infection prophylaxis to significantly impact human health. These studies will lay the foundation for prototypic nanomaterials-based immunization platforms to elicit robust mucosal CD8+T cell immunity, which can be adapted to combat numerous mucosal pathogens.

描述（由适用提供）：粘膜时机中引起稳健记忆CD8+T细胞反应的免疫策略对于促进促进阳性感染的早期遏制很重要，因为估计有70％的病原体通过粘膜表面引发感染。尽管中和抗体反应是保护的临床相关性，但已证明组织居留的记忆CD8+T细胞通过立即识别和杀死感染细胞来预防感染。因此，粘膜免疫化策略能够引起靶性粘膜组织中稳健记忆CD8+T细胞种群的粘膜免疫策略。但是，成功发展粘膜疫苗的主要限制因素是缺乏有效且安全的免疫调节剂。在当前项目中，我们将开发和研究自组装肽纳米材料对引发受保护的粘膜CD8+T细胞反应的结核分枝杆菌（MTB），这是全球主要的健康伯恩。我们将利用与结核分枝杆菌（MTB）相关的自组装肽（MTB）与抗原表位相关的肽纳米纤维，并研究小鼠鼻内免疫抑制后的效应子和记忆CD8+T细胞反应。在AIM 1中，我们将单独合成具有天然CD8+T细胞表位的肽纳米纤维，或与MTB特异性CD4+T助手表位共同组装，以在肺中引起可靠的细胞免疫史。具有较强免疫原性的配方将测试使用模拟的MTB挑战，以防止感染 MTB感染的自然途径。肺，肝脏和其他器官的细菌负荷将确定评估保护。在AIM 2中，我们将从AIM 1中将合成Toll样受体（TLR）激动剂纳入保护性肽纳米纤维疫苗配方中，以扩大具有多功能回忆活动的记忆CD8+T细胞种群。粘膜和全身效应子以及记忆反应将在鼻内递送纳米纤维疫苗后确定，并使用雾化的MTB模型评估保护的增强。拟议工作的完成将整合合成化学，纳米技术，免疫学和预防感染的领域，以显着影响人类健康。这些研究将为基于纳米材料的原型免疫抑制平台奠定基础，以引起强大的粘膜CD8+T细胞免疫学，可以适应以应对许多粘膜病原体。