Xie Min, Tsai Chen-Yu, Woo Joshua, Nuritdinov Frank, Cristaldo Melissa, Odjourian Narineh M, Antilus-Sainte Rosleine, Dougher Maureen, Gengenbacher Martin
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States.
Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, United States.
Front Immunol. 2025 Feb 6;16:1551183. doi: 10.3389/fimmu.2025.1551183. eCollection 2025.
Bacille Calmette-Guérin (BCG), the only tuberculosis vaccine currently in clinical use, provides inadequate long-term protection. Administered at birth, BCG induces broad immune responses against a large number of antigens shared with (Mtb), but protection wanes over time. We have previously shown that unconventional B cell subsets play a role in tuberculosis control.
High-dimensional flow cytometry and multiplex cytokine analysis were employed to investigate the effects of immunotherapy on BCG-vaccinated mice in an Mtb challenge model.
In this study, we investigate the potential of recombinant cytokines targeting B cells - B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) - to modulate BCG immunity and improve protection in mice. Both cytokines play overlapping roles in B cell development and peripheral survival. Following subcutaneous BCG vaccination, immunotherapy with BAFF or APRIL resulted in an increased frequency of unconventional B cells potentially transitioning into antibody-producing plasma cells. Concurrently, we observed an increased frequency of central memory T cells, a subset critical for protective immunity. Changes in cellular immune responses were accompanied by reduced pro-inflammatory cytokine profiles and a contraction of the leukocyte population in lungs. Importantly, mice receiving BCG vaccination followed by BAFF or APRIL immunotherapy exhibited superior long-term protection against pulmonary tuberculosis relative to controls that received only BCG.
In summary, our findings demonstrate that combining BCG vaccination with B cell targeted immunomodulatory therapies can improve long-term protection against pulmonary tuberculosis, highlighting the continued relevance and underutilized potential of BCG as a vaccine platform.
卡介苗（BCG）是目前临床上唯一使用的结核病疫苗，其提供的长期保护作用不足。卡介苗在出生时接种，可诱导针对与结核分枝杆菌（Mtb）共有的大量抗原产生广泛的免疫反应，但随着时间的推移保护作用会减弱。我们之前已经表明，非常规B细胞亚群在结核病控制中发挥作用。
采用高维流式细胞术和多重细胞因子分析来研究免疫疗法对结核分枝杆菌攻击模型中接种卡介苗小鼠的影响。
在本研究中，我们研究了靶向B细胞的重组细胞因子——B细胞活化因子（BAFF）和增殖诱导配体（APRIL）——调节卡介苗免疫并改善小鼠保护作用的潜力。这两种细胞因子在B细胞发育和外周存活中发挥重叠作用。皮下接种卡介苗后，用BAFF或APRIL进行免疫治疗导致可能转变为产生抗体的浆细胞的非常规B细胞频率增加。同时，我们观察到中央记忆T细胞频率增加，中央记忆T细胞是保护性免疫的关键亚群。细胞免疫反应的变化伴随着促炎细胞因子谱的降低和肺部白细胞群体的收缩。重要的是，与仅接种卡介苗的对照组相比，接种卡介苗后接受BAFF或APRIL免疫治疗的小鼠对肺结核表现出更好的长期保护作用。
总之，我们的研究结果表明，将卡介苗接种与靶向B细胞的免疫调节疗法相结合可以提高对肺结核的长期保护作用，突出了卡介苗作为疫苗平台的持续相关性和未充分利用的潜力。
