Defining the Correlates of Bactericidal Immunity in Tuberculosis

定义结核病杀菌免疫的相关性

• 批准号: 8207834
• 负责人: Steven A Porcelli
• 金额: $ 20.81万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207834
• 关键词: Address; Adoptive Transfer; Animals; Antigens; Area; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cell surface; Cells; Cessation of life; Characteristics; Communicable Diseases; Country; Development; Engineering; Environment; Escherichia coli; Extreme drug resistant tuberculosis; Funding; Genes; Goals; Hand; Immune Sera; Immune system; Immunity; Immunization; Immunotherapeutic agent; Intervention; Laboratories; Licensing; Medicine; Methods; Morbidity - disease rate; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Organism; Pharmaceutical Preparations; Phenotype; Planets; Population; Prevention; Production; Proteins; Protocols documentation; Recombinant Proteins; Recombinants; Research; Specificity; Sterilization; System; T cell response; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Tissues; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccines; Virulent; Work; bactericidal immunity; bactericide; college; cytokine; design and construction; direct application; foot; global health; improved; killings; memory CD4 T lymphocyte; mortality; mycobacterial; novel; novel strategies; programs; public health relevance; response; tool; tuberculosis immunity; vaccination against tuberculosis

DESCRIPTION (provided by applicant): Tuberculosis remains one of the most significant global causes of morbidity and mortality from infectious disease, and an effective vaccine for controlling Mycobacterium tuberculosis (Mtb) has yet to be found. Well established correlates of vaccine induced protection against Mtb have not been established, and it remains to be shown that the immune system is capable of achieving high levels of bactericidal immunity against this organism. Along with our colleagues in the tuberculosis research group at Einstein, we have recently produced and characterized a genetically engineered form of the rapidly growing nonpathogenic M. smegmatis that can induce an extraordinary and unprecedented level of protective immunity in mice against Mtb. Initial studies show that mice immunized with this M. smegmatis strain, which we designate IKE+, can respond to challenges by virulent Mtb with rapid induction of a high level of bactericidal immunity. This is associated with unprecendented reductions in tissue bacterial levels, and in some cases even complete sterilization of tissues with apparent cure of tuberculosis. Preliminary adoptive transfer studies show that this immunity is dependent on a population of memory CD4+ T cells, which are able to transfer a significant level of the bactericidal response to naove animals. Furthermore, the induction of this population of CD4+ T cells appears to be dependent on the presence of B cells in the immunizing environment. These findings define a new experimental system in which to seek correlates of bactericidal immunity against M. tuberculosis, which we will use to identify the characteristics of the specific T cell populations that are capable of inducing the remarkable anti-mycobacterial responses. In this two year project, we propose to identify the phenotype and antigen specificities of the relevant T cell populations, and extensively characterize their functional activities with respect to production of key cytokines and other effector molecules. These studies are likely to reveal previously unexplored mechanisms by which the immune system can control and eliminate Mtb, and have potentially major implications for development of tuberculosis vaccines. PUBLIC HEALTH RELEVANCE: Tuberculosis remains one of the most important global causes of morbidity and mortality from infectious disease. This proposal is an integral component of a program that aims to understand in greater detail the mechanisms by which the immune system can be made to recognize and kill Mycobacterium tuberculosis following specific immunization with novel experimental vaccines. The goal of the research is to establish principles that will enable the design and construction of better vaccines for the prevention of tuberculosis.

描述（由申请人提供）：结核病仍然是全球传染病发病和死亡的最重要原因之一，控制结核分枝杆菌（Mtb）的有效疫苗尚未发现。疫苗诱导的抗结核分枝杆菌保护的相关因素尚未确定，免疫系统是否能够对这种生物体产生高水平的杀菌免疫仍有待证实。我们与爱因斯坦大学结核病研究小组的同事们一起，最近研制出了一种快速生长的非致病性耻垢分枝杆菌的基因工程形式，并对其进行了鉴定，这种基因工程形式可以在小鼠体内诱导出非同寻常的、前所未有的对结核分枝杆菌的保护性免疫。初步研究表明，用这种耻垢分枝杆菌菌株（我们称之为IKE+）免疫的小鼠，可以通过快速诱导高水平的杀菌免疫来应对毒力强的结核分枝杆菌的攻击。这与组织细菌水平前所未有的减少有关，在某些情况下，甚至可以在明显治愈结核病的情况下对组织进行完全消毒。初步过继性转移研究表明，这种免疫依赖于记忆性CD4+ T细胞群，它们能够将相当程度的杀菌反应转移给幼稚动物。此外，CD4+ T细胞群的诱导似乎依赖于免疫环境中B细胞的存在。这些发现定义了一个新的实验系统，在这个系统中，我们将寻求对结核分枝杆菌的杀菌免疫的相关性，我们将用它来确定能够诱导显著的抗分枝杆菌反应的特定T细胞群的特征。在这个为期两年的项目中，我们建议鉴定相关T细胞群的表型和抗原特异性，并广泛表征它们在产生关键细胞因子和其他效应分子方面的功能活动。这些研究很可能揭示免疫系统控制和消除结核分枝杆菌的机制，并对结核病疫苗的开发具有潜在的重大意义。