Lei Qing, Fu Hui, Yao Zongjie, Zhou Zijie, Wang Yueqing, Lin Xiaosong, Yuan Yin, Ouyang Qi, Xu Xinyue, Cao Jinge, Gan Mengze, Fan Xionglin
Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China.
Departement of Infectious Disease, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
J Transl Med. 2024 Dec 4;22(1):1103. doi: 10.1186/s12967-024-05683-w.
The Bacillus Calmette-Guérin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccine candidates. To effectively control the persistent epidemic of adult TB, it is imperative to investigate the mechanisms responsible for the suboptimal efficacy of the BCG prime-boosting strategy against primary Mycobacterium tuberculosis (M.tb) infection.
C57BL/6J mice were immunized with the BCG vaccine either once or twice, followed by analysis of lung tissue to assess changes in cytokine levels. Additionally, varying intervals between vaccinations and detection times were examined to study IL-10 expression across different organs. IL-10-expressing cells in the lungs, spleen, and lymph nodes were analyzed through FACS and intracellular cytokine staining (ICS). BCG-revaccinated IL-10 mutant mice were compared with wild-type mice to evaluate antigen-specific IgG antibody and T cell responses. Protection against M.tb aerosol challenge was evaluated in BCG-revaccinated mice, either untreated or treated with anti-IL-10R monoclonal antibody.
IL-10 was significantly upregulated in the lungs of BCG-revaccinated mice shortly after the booster immunization. IL-10 expression peaked in the lungs 3-6 weeks post-revaccination and was also detected in lymph nodes and spleen as early as 2 weeks following the booster dose, regardless of the intervals between the prime and booster vaccinations. The primary sources of IL-10 in these tissues were identified as macrophages and dendritic cells. Blocking IL-10 signaling in BCG-revaccinated mice-either by using IL-10 mutant mice or administering anti-IL-10R monoclonal antibody increased levels of antigen-specific IFN-γ or IL-2 CD4 T cells, enhanced central and effector memory CD4 T cell responses, and provided better protection against aerosol infection with 300 CFUs of M.tb.
Our findings are crucial for formulating effective immunization strategies related to the BCG vaccine and for developing efficacious adult TB vaccines.
卡介苗（BCG）疫苗是目前唯一被授权用于预防结核病（TB）的疫苗，即便作为加强针使用卡介苗本身或异源候选疫苗，其在保护青少年和成年人免受活动性结核病侵害方面的效果也有限。为有效控制成人结核病的持续流行，必须探究卡介苗初免 - 加强策略针对原发性结核分枝杆菌（M.tb）感染效果欠佳的机制。
对C57BL / 6J小鼠进行一次或两次卡介苗疫苗免疫，随后分析肺组织以评估细胞因子水平的变化。此外，研究了不同的疫苗接种间隔和检测时间，以研究不同器官中白细胞介素 - 10（IL - 10）的表达情况。通过流式细胞术（FACS）和细胞内细胞因子染色（ICS）分析肺、脾和淋巴结中表达IL - 10的细胞。将再次接种卡介苗的IL - 10突变小鼠与野生型小鼠进行比较，以评估抗原特异性IgG抗体和T细胞反应。在再次接种卡介苗的小鼠中，评估未处理或用抗IL - 10R单克隆抗体处理的小鼠对M.tb气溶胶攻击的保护作用。
在加强免疫后不久，再次接种卡介苗的小鼠肺中IL - 10显著上调。IL - 10表达在再次接种后3 - 6周在肺中达到峰值，并且早在加强剂量后2周就在淋巴结和脾脏中检测到，无论初免和加强接种之间的间隔如何。这些组织中IL - 10的主要来源被确定为巨噬细胞和树突状细胞。通过使用IL - 10突变小鼠或施用抗IL - 10R单克隆抗体来阻断再次接种卡介苗小鼠中的IL - 10信号传导，可增加抗原特异性干扰素 - γ（IFN - γ）或白细胞介素 - 2（IL - 2）CD4 T细胞的水平，增强中央和效应记忆CD4 T细胞反应，并为300个菌落形成单位（CFU）的M.tb气溶胶感染提供更好的保护。
我们的研究结果对于制定与卡介苗疫苗相关的有效免疫策略以及开发有效的成人结核病疫苗至关重要。
