Harnessing B cells for TB vaccine development to improve therapy of TB and TB-HIV coinfection

利用 B 细胞开发结核病疫苗，以改善结核病和结核病-艾滋病毒合并感染的治疗

基本信息

批准号：
10441411
负责人：
Martin Alfons Gengenbacher
金额：
$ 129.44万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441411
关键词：
Adult Animal Model Animals Apoptosis Area Attenuated Attenuated Vaccines Autophagocytosis B-Cell Development B-Lymphocyte Subsets B-Lymphocytes BCG Live BCG Vaccine Blood Blood Circulation Cells Childhood Clinical Complement Containment Data Development Drug resistance Exposure to Face Flow Cytometry Frequencies Genes Genetic Genetic Engineering HIV HIV therapy HIV/TB Human Immunodeficient Mouse Immunologics Immunophenotyping Individual Infection Infection prevention Ligands Longevity Lung Measures Memory Modeling Monitor Mus Mycobacterium bovis Mycobacterium tuberculosis Organ Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Pre-Clinical Model Recombinants Recurrence Regimen Relapse Research Role Route Safety T cell response T-Lymphocyte Testing Therapeutic Time Treatment Efficacy Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccine Research Vaccines Virus Diseases adaptive immunity antiretroviral therapy chemotherapy child protection co-infection cohort cytokine experimental study genetic resistance genetic vaccination immunogenic immunogenicity immunoregulation improved infected B cell innovation knock-down macrophage mouse model mutant mycobacterial next generation novel pathogen prevent prophylactic protective efficacy rBCG reactivation from latency receptor response safety assessment therapeutic vaccine tuberculosis drugs tuberculosis treatment vaccine candidate vaccine development vaccine evaluation

项目摘要

Abstract Current tuberculosis (TB) control in the presence or absence of human immunodeficiency virus (HIV) infection is suboptimal: Bacillus Calmette-Guérin (BCG), the sole TB vaccine in clinical use, provides only limited protection during childhood and multi-drug chemotherapy faces challenges due to the alarming spread of drug resistance. An integrated approach combining chemotherapy with a therapeutic vaccine given after exposure to Mycobacterium tuberculosis (Mtb) could be a way forward. TB vaccine research mostly focused on prophylactic candidates aiming to prevent infection. Therapeutic TB vaccines with novel mechanisms of action are needed (i) to complement existing chemotherapy and prevent relapse thereafter, and (ii) to cure latent TB infection (LTBI) or prevent reactivation. T lymphocytes are critical for the control of TB infection and the specific T cell response elicited by a vaccine has been used as a key correlate of immunogenicity. In contrast, B cells are understudied in all areas of TB research. Using a deep immunophenotyping approach, our preliminary data in mice suggest that TB infection leads to dramatic changes in the landscape of B cell subpopulations. We identified a novel B cell subset with marginal zone (MZ) phenotype that was activated, had a memory phenotype and expressed receptors recognizing the human cytokines A Proliferation-Inducing Ligand, APRIL, and B cell Activating Factor, BAFF, critical for B cell development and survival. Functional studies indicated that murine MZ B cells contributed to Mtb containment in mice. Surprisingly, these B cells expressed a panel of Th1 cytokines, well studied in T cells, suggesting a possible role in the first line of defense against TB infection. We found that MZ B cells were depleted in blood of TB patients and TB/HIV coinfected people. Our hypothesis is that MZ B cells can be restored by antitubercular therapy and harnessed for TB vaccine development. To test this, we genetically engineered BCG to express the human cytokines APRIL and BAFF that stimulate development and longevity of BAFF receptor- and APRIL receptor-expressing B cells, including MZ B cells. We will determine the safety, immunogenicity and prophylactic efficacy in mice. The therapeutic efficacy will be evaluated in two novel innovative mouse models that allow us to determine the capacity of cytokine expression in BCG strains to prevent relapse after drug treatment and to reduce the reactivation frequency of paucibacillary TB mimicking aspect of LTBI in humans. We will determine the frequency of MZ B cells in peripheral blood mononuclear cells (PBMC) from people having LTBI and TB, across HIV status, including antitubercular and antiretroviral therapy. We will stimulate PBMC of the same cohorts with cytokine-expressing BCG strains to study the immunological consequences and to demonstrate, in principle, the feasibility of these vaccines during therapy of TB, HIV and TB/HIV coinfection. We will monitor the global landscapes of T cells and B cells by high parameter flow cytometry to define immunological correlates of TB infection and vaccine protection. Our proposal will determine whether B cells can be harnessed by cytokine-secreting B cell-targeting BCG vaccines for TB vaccine development.

抽象的在存在或不存在人类免疫缺陷病毒（HIV）感染的情况下，目前的结核病（TB）控制是次优的：bacillus calmette-guérin（BCG），唯一的结核病疫苗在临床使用中，仅提供有限的由于药物的散布令人震惊，儿童期和多药化疗期间的保护面临挑战反抗。一种综合方法，将化学疗法与接触后的治疗疫苗结合结核分枝杆菌（MTB）可能是前进的道路。结核病疫苗研究主要集中于预防性候选人旨在防止感染。需要具有新型作用机理的治疗性结核病疫苗（i）完成现有的化学疗法并防止救济，以及（ii）治愈潜在的结核病感染（LTBI）或防止重新激活。 T淋巴细胞对于控制结核病感染和特定T细胞反应至关重要通过疫苗引起的已被用作免疫原性的关键相关性。相反，B细胞被理解在结核病研究的所有领域。使用深层免疫表型方法，我们在小鼠中的初步数据表明结核病感染导致B细胞亚群的景观发生巨大变化。我们确定了一个小说b 具有激活，具有记忆表型并表达的边缘区（MZ）表型的细胞子集识别人类细胞因子的受体诱发了增殖的配体，4月和B细胞激活因子， BAFF，对于B细胞发育和生存至关重要。功能研究表明，鼠MZ B细胞有助于到小鼠中的MTB遏制。令人惊讶的是，这些B细胞表达了一组Th1细胞因子，在T 细胞，表明在针对结核病感染的第一道防线中可能起作用。我们发现MZ B细胞是在结核病患者和结核病/艾滋病毒共同感染的人的血液中耗尽。我们的假设是可以恢复MZ B细胞通过抗结核疗法并利用用于结核病疫苗的开发。为了测试这一点，我们一般设计 BCG表达人类细胞因子四月和刺激Baff的发展和寿命的BAFF 受体和四月表达受体的B细胞，包括MZ B细胞。我们将确定安全性小鼠的免疫原性和预防效率。治疗效率将在两种新颖创新的小鼠模型，使我们能够确定BCG菌株中细胞因子表达的能力以防止药物治疗后复发并减少模仿paucibaCillarry TB的重新激活频率人类的ltbi。我们将确定外周血单核细胞中MZ B细胞的频率（PBMC）来自患有LTBI和结核病的人，包括抗结核病和抗逆转录病毒疗法。我们将刺激与表达细胞因子的BCG菌株的同一队列的PBMC，以研究免疫学原则上的后果并证明了这些疫苗在结核病，艾滋病毒和艾滋病毒治疗期间的可行性结核病/HIV共感染。我们将通过高参数流式细胞仪监测T细胞和B细胞的全局景观定义结核病感染和疫苗保护的免疫学相关性。我们的建议将决定是否 B细胞可以通过分泌B细胞靶向BCG疫苗来利用BCG疫苗来利用。