Hwang Shen-An, Kruzel Marian L, Actor Jeffrey K
Department of Pathology, Medical School, University of Texas-Houston Medical School, Houston, TX, USA.
Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, TX, USA.
Int J Immunopathol Pharmacol. 2015 Dec;28(4):452-68. doi: 10.1177/0394632015599832. Epub 2015 Aug 27.
Lactoferrin (LF), an iron binding protein with immune modulatory activities, has adjuvant activity to enhance vaccine efficacy. Tuberculosis (TB) is a pulmonary disease caused by the pathogen Mycobacterium tuberculosis (MTB). Progressive TB disease is clinically defined by damaging pulmonary pathology, a result of inflammation due to immune reactivity. The current vaccine for TB, an attenuated strain of Mycobacterium bovis, Bacillus Calmette Guerin (BCG), has only limited efficacy to prevent adult pulmonary TB. This study examines a Chinese hamster ovary (CHO) expressed recombinant human LF (rHLF) to boost efficacy of the BCG vaccine and delay early pathology post infectious challenge. C57BL/6 mice were immunized with BCG, or BCG admixed with either rHLF or bovine LF (bLF; internal control), or remained unvaccinated. Mice were then aerosol challenged with Erdman MTB. All vaccinated mice demonstrated decreased organ bacterial load up to 19 weeks post infection compared with non-vaccinated controls. Furthermore, mice receiving bLF or rHLF supplemented BCG vaccines showed a modest decrease in lung pathology developed over time, compared to the BCG vaccine alone. While mice vaccinated with BCG/rHLF demonstrated increased general lung inflammation at day 7, it occurred without noticeable increase in pro-inflammatory cytokines. At later times, decreased pathology in the rHLF groups correlated with decreased inflammatory cytokines. Splenic recall to BCG antigens showed BCG/rHLF vaccination increased production of IFN-γ, IL-6, and GM-CSF compared to naïve, BCG, and BCG/bLF groups. Analysis of T cell stimulating functions of bone marrow derived macrophages and dendritic cells treated with BCG/bLF or BCG/rHLF showed decreases in IL-10 production when co-cultured with sensitized CD4 and CD8 T cells, compared to those cultured with macrophages/dendritic cells treated with BCG without LF. These results indicate that addition of rHLF to the BCG vaccine can modulate development of host pathology early post infectious challenge, most likely through host immune regulation affecting hypersensitive responses.
乳铁蛋白（LF）是一种具有免疫调节活性的铁结合蛋白，具有增强疫苗效力的佐剂活性。结核病（TB）是由病原体结核分枝杆菌（MTB）引起的肺部疾病。进展性结核病在临床上表现为肺部病理损伤，这是免疫反应引起炎症的结果。目前用于结核病的疫苗是牛分枝杆菌减毒株卡介苗（BCG），其预防成人肺结核的效力有限。本研究检测了中国仓鼠卵巢（CHO）表达的重组人乳铁蛋白（rHLF），以提高卡介苗疫苗的效力，并延缓感染攻击后的早期病理变化。将C57BL/6小鼠用卡介苗免疫，或用卡介苗与rHLF或牛乳铁蛋白（bLF；内部对照）混合免疫，或不进行疫苗接种。然后用埃尔德曼结核分枝杆菌对小鼠进行气溶胶攻击。与未接种疫苗的对照组相比，所有接种疫苗的小鼠在感染后长达19周时器官细菌载量均降低。此外，与单独使用卡介苗疫苗相比，接受添加bLF或rHLF的卡介苗疫苗的小鼠随着时间的推移肺部病理变化有适度降低。虽然接种卡介苗/rHLF的小鼠在第7天出现肺部炎症普遍增加，但促炎细胞因子没有明显增加。在后期，rHLF组病理变化的减少与炎性细胞因子的减少相关。对卡介苗抗原的脾脏回忆反应显示，与未免疫、卡介苗和卡介苗/bLF组相比，接种卡介苗/rHLF可增加IFN-γ、IL-6和GM-CSF的产生。对用卡介苗/bLF或卡介苗/rHLF处理的骨髓来源巨噬细胞和树突状细胞的T细胞刺激功能分析显示，与用不含LF的卡介苗处理的巨噬细胞/树突状细胞共同培养时相比，与致敏CD4和CD8 T细胞共同培养时IL-10产生减少。这些结果表明，在卡介苗疫苗中添加rHLF可以在感染攻击后早期调节宿主病理变化的发展，最有可能是通过影响超敏反应的宿主免疫调节来实现的。
