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：
10662211
负责人：
Martin Alfons Gengenbacher
金额：
$ 127.65万
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/10662211
关键词：
Adult Animal Model Animals Area Attenuated Vaccines B-Cell Activation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes BCG Live BCG Vaccine Blood Cell secretion Cells Child Childhood Circulation Clinical Combination Drug Therapy 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 Inhibition of Apoptosis Ligands Longevity Lung Macrophage Measures Memory Modeling Monitor Mus Mycobacterium bovis Mycobacterium tuberculosis Organ Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Pre-Clinical Model Proliferating 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 co-infection cohort cytokine experimental study genetic resistance humoral immunity deficiency immunogenic immunogenicity immunoregulation improved infected B cell inhibition of autophagy innovation knock-down mouse model mutant mycobacterial next generation novel pathogen prevent prophylactic protective efficacy rBCG reactivation from latency receptor relapse prevention 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) 感染的情况下当前的结核病 (TB) 控制次优：卡介苗 (BCG) 是临床使用的唯一结核病疫苗，仅提供有限的由于药物扩散惊人，儿童期和多药物化疗的保护面临挑战一种将化疗与接触后给予治疗性疫苗相结合的综合方法。结核分枝杆菌 (Mtb) 可能是结核病疫苗研究的一个方向，主要集中在预防性疫苗上。需要具有新颖作用机制的治疗性结核疫苗。 (i) 补充现有化疗并预防其后复发，以及 (ii) 治愈潜伏性结核感染 (LTBI) 预防或重新激活 T 淋巴细胞对于控制结核感染和特异性 T 细胞反应至关重要。疫苗引起的免疫反应已被用作免疫原性的关键相关因素，相比之下，B 细胞的研究还不够充分。我们在小鼠身上的初步数据表明，使用深度免疫表型分析方法，可以在结核病研究的所有领域中发挥作用。结核病感染导致 B 细胞亚群格局发生巨大变化我们发现了一种新的 B 细胞。具有边缘区（MZ）表型的细胞亚群被激活，具有记忆表型并表达识别人类细胞因子 A 增殖诱导配体、APRIL 和 B 细胞激活因子的受体， BAFF，对 B 细胞发育和存活至关重要，功能研究表明小鼠 MZ B 细胞有贡献。令人惊讶的是，这些 B 细胞表达了一组 Th1 细胞因子，这在 T 细胞中得到了充分研究。细胞，表明 MZ B 细胞可能在抵抗结核感染的第一道防线中发挥作用。结核病患者和结核病/艾滋病毒合并感染者的血液中的 MZ B 细胞可以恢复。为了测试这一点，我们进行了基因工程。 BCG 表达人类细胞因子 APRIL 和 BAFF，刺激 BAFF 的发育和寿命我们将确定表达受体和 APRIL 受体的 B 细胞，包括 MZ B 细胞的安全性。小鼠的免疫原性和预防效果将在两篇小说中进行评估。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，以预防药物治疗后复发并减少少杆菌结核的再激活频率我们将确定外周血单核细胞 (PBMC) 中 MZ B 细胞的频率。 LTBI 和 TB 患者的艾滋病毒感染状况，包括抗结核和抗逆转录病毒治疗。用表达细胞因子的 BCG 菌株刺激同一队列的 PBMC，以研究免疫学后果，并原则上证明这些疫苗在结核病、艾滋病毒和艾滋病毒治疗期间的可行性我们将通过高参数流式细胞术监测 T 细胞和 B 细胞的整体状况。确定结核病感染和疫苗保护的免疫学相关性，我们的建议将确定是否如此。 B 细胞可通过分泌细胞因子的 B 细胞靶向 BCG 疫苗来开发结核疫苗。