Table_1_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.

关于躯体轴对免疫系统精确影响的讨论依然颇具争议。我们先前研究发现，泛发性消融生长激素释放激素（GHRH）基因（Ghrh−/−）的小鼠，其胸腺和T细胞发育正常，但表现出明显的脾脏萎缩和B细胞淋巴细胞性减少。因此，在本研究中，我们探讨了Ghrh−/−小鼠对肺炎链球菌（携带T非依赖性抗原的病原体）的疫苗接种和抗感染反应。Ghrh−/−小鼠在接种原生肺炎球菌多糖（PPS，PPV23）或蛋白-PPS接合物（PCV13）后，均无法触发特定IgM的产生。Ghrh−/−小鼠通过补充生长激素，恢复了针对PPV23疫苗的IgM反应，但对PCV13疫苗则无此效果，这表明生长激素可能对脾脏边缘区产生特异性影响，该区域与对肺炎球菌多糖的T非依赖性反应密切相关。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的易感性，肺内细菌负荷随时间推移而增加，并在24小时内出现致死性菌血症。感染Ghrh−/−小鼠的肺部被大量炎症巨噬细胞和中性粒细胞浸润，而肺B细胞显著减少。炎症转录特征在Ghrh−/−小鼠中显著升高。在此动物模型中，躯体轴的GHRH/GH/IGF1轴在疫苗和免疫防御肺炎链球菌方面发挥着至关重要且出乎意料的角色。