Generation of high avidity mucosal T cell responses

产生高亲合力粘膜 T 细胞反应

• 批准号: 6590039
• 负责人: ALISTAIR John RAMSAY
• 金额: $ 21.3万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590039
• 关键词: AIDS vaccines; Adenoviridae; Poxviridae; biotechnology; cell migration; cytotoxic T lymphocyte; immunologic memory; laboratory mouse; leukocyte activation /transformation; mucosal immunity; ovalbumin; passive immunization; recombinant virus; vaccine development; vector vaccine

DESCRIPTION (provided by applicant): Although HIV spreads systemically, the majority of infections are transmitted at mucosal surfaces, hence a vaccine should ideally induce protective local immunity. Furthermore, it is now widely felt that potent antiviral cytotoxic T lymphocytes (CTL) should be a major component of any immune response that is induced by an effective vaccine against HIV/AIDS. In this context, it is becoming increasingly apparent that not only the magnitude but also the quality of the T cell response may be important for protection against some pathogens, particularly those proven to be resistant to existing immunization strategies. T cells that show high levels of sensitivity to antigen are said to have 'high functional avidity' and may have the capacity to recognize infected cells very early in infection leading to more efficient recovery or to protection following vaccination. Unfortunately, there are few vaccination strategies currently available that will direct CTL responses to mucosal surfaces, particularly the genital and rectal tissues where the virus is usually first encountered. In this project, we will evaluate genetic vaccination strategies designed to generate mucosal T cell responses, particularly CTL, of high avidity for the immunizing antigen in key mucosal tissues. In particular, we will consecutively deliver intranasal inocula of DNA vaccines and recombinant poxvirus or adenovirus vectors encoding a model vaccine antigen and compare these approaches in terms of their capacity to generate enhanced mucosal T cell responses. The use of ovalbumin (OVA) as our vaccine antigen will facilitate studies of the development, avidity, persistence and migration of vaccine-induced T cell populations due to the variety of analytical reagents that are available in this system. Systemic use of these vectors in this manner resulted in sustained CTL responses of high avidity that expanded rapidly upon re-exposure to recall antigen but these were not expressed in mucosal tissues. It is in these tissues that strong CTL responses, particularly those of high avidity, would be most effective, with the possibility of mucosal elimination of HIV, preventing subsequent systemic infection and establishment of the virus in the host. The capcity of our mucosal vaccination strategy to focus CTL responses in key mucosal tissues may be critical for mucosal containment of the virus and prevention of systemic spread.

描述（由申请人提供）：尽管艾滋病毒系统地传播，但大多数感染是在粘膜表面传播的，因此疫苗理想地应诱发保护性局部免疫。此外，现在人们普遍认为，有效的抗病毒细胞毒性T淋巴细胞（CTL）应该是任何免疫反应的主要组成部分，该免疫反应是由有效疫苗诱导的针对HIV/AIDS的。在这种情况下，越来越明显的是，不仅幅度，而且T细胞反应的质量对于保护某些病原体，尤其是那些被证明对现有免疫策略具有抵抗力的病原体可能很重要。据说对抗原的敏感性高度敏感的T细胞具有“高功能亲和力”，并且可能在感染中很早就识别感染细胞，从而导致更有效的恢复或在疫苗接种后得到保护。 不幸的是，目前几乎没有疫苗接种策略可以将CTL反应引向粘膜表面，尤其是通常首次遇到病毒的生殖器和直肠组织。在该项目中，我们将评估旨在产生粘膜T细胞反应，特别是CTL的遗传疫苗接种策略，以使关键粘膜组织中的抗原免疫抗原具有高潮。特别是，我们将连续提供DNA疫苗和重组痘病毒或编码模型疫苗抗原的腺病毒量的鼻内接种物，并根据其产生增强的粘膜T细胞反应的能力来比较这些方法。 由于该系统中可用的分析试剂种类繁多，因此将卵蛋白（OVA）用作我们的疫苗抗原将有助于研究疫苗诱导的T细胞群体的发育，持久性和迁移。这些向量以这种方式使用这些载体导致高潮的持续CTL反应，后者在重新暴露以召回抗原后迅速扩展，但在粘膜组织中未表达。正是在这些组织中，强烈的CTL反应，尤其是流长较高的反应将是最有效的，并且可能会消除HIV，从而阻止随后的全身感染和宿主中病毒的建立。我们的粘膜疫苗接种策略将关键的CTL反应集中在关键粘膜组织中的能力可能对于粘膜遏制病毒和预防全身传播至关重要。