Mucosal immunity and rectal challenge

粘膜免疫和直肠挑战

基本信息

批准号：
7882399
负责人：
Joseph John Mattapallil
金额：
$ 85.31万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7882399
关键词：
Address Adjuvant Animals Antibody Formation Blood CD4 Positive T Lymphocytes CD8B1 gene Cells Cohort Effect DNA Development Enteral Generations HIV HIV vaccine HIV-2 Immune response Immune system Immunization Immunologic Deficiency Syndromes Immunologic Memory Infection Interleukin-15 Kinetics Knowledge Macaca mulatta Modeling Mucosal Immune Responses Mucosal Immunity Mucous Membrane Nature Oral mucous membrane structure Outcome Plasma Play Process Recombinants Role Route SIV Small intestine mucous membrane T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Tonsil Vaccinated Vaccination Vaccines Viral Viral Load result Virus Diseases cell killing gastrointestinal memory CD4 T lymphocyte mucosal site mucosal vaccination novel strategies pathogen prevent public health relevance rectal response secondary infection targeted delivery vaccination strategy virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): HIV infection is associated with massive loss of memory CD4 T cells in mucosal tissues such as the gastrointestinal and oral mucosa. These CD4 T cells not only serve as a pool of readily available target cells for propagating HIV infection but are also critical for the generation of anti-viral CD8 T cell responses against previously exposed and opportunistic pathogens. Limited information exists regarding the ability of mucosal vaccination to protect the CD4 T cell compartment in mucosal sites. Recent studies have demonstrated that systemic vaccination induced suboptimal mucosal immune responses that were associated with partial protection of the mucosal CD4 T cells. Given the highly compartmentalized nature of the mucosal immune system it is highly likely that mucosal vaccination can induce stronger immune responses in mucosal tissues than systemic vaccination. The overall objectives of this proposal are to evaluate mucosal vaccination strategies to induce potent immune responses in the mucosa. We hypothesize that mucosal vaccination can induce potent immune responses that can better protect the CD4 T cells in the mucosa after challenge, and this protection will correlate with better long-term outcome. We propose to test this hypothesis using the rhesus macaque model. In Specific aim 1 we will determine if systemic prime/mucosal boost can significantly amplify mucosal immune responses better than systemic boosting. In Specific aim 2 we will determine if alternate mucosal vaccination routes are better at inducing potent immune responses in the mucosa. In Specific aim 3 we propose to vaccinate mucosally with adjuvants to determine if it can potentiate immune responses in the mucosa that better correlate with protection. Overall these studies will allow us to delineate the role of vaccine induced mucosal immunity in protecting the mucosa CD4 T cell compartment from infection leading to better long-term outcome. PUBLIC HEALTH RELEVANCE: HIV causes immunodeficiency very rapidly by killing the cells it infects. Protecting these cells from infection is critical to prevent the devastating effect of HIV infection and the onset of secondary infections. This project explores the role of mucosal vaccination in protecting cells from getting infected with HIV thereby leading to a better long-term survival outcome. The studies proposed here will aid in the development of an effective vaccine against HIV.

描述（由申请人提供）：HIV感染与粘膜组织（例如胃肠道和口服粘膜）中记忆CD4 T细胞的大规模丧失有关。这些CD4 T细胞不仅可以用作易近可用的靶细胞来传播HIV感染，而且对于针对先前暴露和机会性病原体的抗病毒CD8 T细胞反应的产生也至关重要。关于粘膜疫苗接种保护粘膜部位CD4 T细胞室的能力的信息有限。最近的研究表明，全身疫苗接种诱导的次优粘膜免疫反应与粘膜CD4 T细胞的部分保护有关。鉴于粘膜免疫系统的高度分室性质，粘膜疫苗接种很可能与全身性疫苗相比，粘膜疫苗接种可以诱导粘膜组织中更强的免疫反应。该提案的总体目标是评估粘膜疫苗接种策略，以诱导粘膜中有效的免疫反应。我们假设粘膜疫苗接种可以诱导有效的免疫反应，从而在挑战后更好地保护粘膜中CD4 T细胞，并且这种保护将与更好的长期结果相关。我们建议使用恒河猕猴模型检验这一假设。在特定的目标1中，我们将确定系统性质量/粘膜升高是否可以比全身性增强更好地扩大粘膜免疫反应。在特定目标2中，我们将确定替代粘膜疫苗接种途径是否更好地诱导粘膜中的有效免疫反应。在特定目标3中，我们建议与佐剂接种粘液疫苗，以确定它是否可以增强粘膜中的免疫反应，从而更好地与保护相关。总体而言，这些研究将使我们能够描述疫苗诱导的粘膜免疫在保护粘膜CD4 T细胞室免受感染中的作用，从而获得更好的长期预后。公共卫生相关性：艾滋病毒通过杀死其感染的细胞非常迅速地引起免疫缺陷。保护这些细胞免受感染至关重要，对于防止HIV感染的毁灭性作用和继发性感染的发作至关重要。该项目探讨了粘膜疫苗接种在保护细胞免于感染HIV的作用，从而导致更好的长期生存结果。这里提出的研究将有助于开发针对HIV的有效疫苗。