Table_2_Growth Hormone (GH) Deficient Mice With GHRH Gene Ablation Are Severely Deficient in Vaccine and Immune Responses Against Streptococcus pneumoniae.pdf

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh−/−) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh−/− mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh−/− mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh−/− mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh−/− mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh−/− mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh−/− mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae.

关于体轴对免疫系统精确影响的争论至今仍未平息。我们先前研究发现，生长激素释放激素（GHRH）基因（Ghrh−/−）广泛敲除的小鼠其胸腺和T细胞发育正常，但表现出显著的脾脏萎缩和B细胞淋巴减少。因此，在本研究中，我们探讨了Ghrh−/−小鼠针对携带T非依赖性抗原的肺炎链球菌的疫苗接种和抗感染反应。Ghrh−/−小鼠在接受天然肺炎球菌多糖（PPS，PPV23）或蛋白-PPS偶联物（PCV13）疫苗接种后，无法诱导特定IgM的产生。Ghrh−/−小鼠接受生长激素补充后，IgM对PPV23疫苗的反应得以恢复，但对PCV13疫苗的反应则无改善，这表明生长激素可能对脾脏边缘带产生特定的作用，而该区域在针对肺炎球菌多糖的T非依赖性反应中扮演着至关重要的角色。正如预期，在给予低剂量肺炎链球菌后，野生型（WT）小鼠在24小时内完全清除细菌。与此形成鲜明对比的是，Ghrh−/−小鼠对肺炎链球菌感染表现出显著易感性，肺内细菌载量随时间推移而增加，并在24小时后出现致命的败血症。感染Ghrh−/−小鼠的肺部大量浸润炎症巨噬细胞和中性粒细胞，而肺内B细胞显著减少。Ghrh−/−小鼠的炎症转录组特征显著升高。在本动物模型中，体轴GHRH/GH/IGF1轴在针对肺炎链球菌的疫苗接种和免疫防御中发挥着至关重要且出乎意料的角色。