N-乙酰半胱氨酸治疗COPD合并肺结核临床观察

目的：评价N-乙酰半胱氨酸（NAC）对慢性阻塞性肺疾病（COPD）合并肺结核患者肺功能、细胞免疫功能和生活质量的影响。方法：93例患者随机分为对照组47例和观察组46例，对照组予常规治疗，观察组加服NAC，6个月为一个疗程。比较抗结核作用、肺功能、细胞免疫功能和生活质量，记录不良反应。结果：治疗后，与对照组相比，观察组肺功能指标FEV₁/FVC和PEF，CD4+T、CD4+Foxp3+调节性T细胞亚群比例明显升高，CD4+/CD8+和SGRQ问卷中症状、活动、影响维度评分明显降低，组间均有显著性差异（P<0.05）。其余指标组间无差异。结论：NAC可明显改善COPD合并肺结核患者的肺功能、细胞免疫功能和生活质量，值得临床推广。     

Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.     

中药调节黏膜免疫系统用于防治COVID-19的思路探索

机体免疫功能低下患者,极易出现新型冠状病毒感染,与中医所说正气不足、邪毒侵扰一致。目前集中在抗病毒药物研发是必须的,但对于调节机体免疫系统制剂的研究也较为迫切。黏膜组织是人体免疫系统的一道重要屏障,具有独特功能和结构的独立免疫体系,是机体抵抗感染的第一道防线,与外界抗原(比如食物、共生菌、病毒等)直接接触。其在抵抗病毒、抗感染方面,黏膜免疫(如呼吸道黏膜、肠道黏膜等)起着极其重要的作用,可以消灭外来病原微生物或其他外来抗原,不至于病毒侵入机体组织而对机体造成损伤。中药通过黏膜免疫系统发挥治疗作用的研究报道日益增多,该文拟针对黏膜免疫系统与新型冠状病毒肺炎(COVID-19)的关系以及中药的干预机制展开探讨,以期为COVID-19的防治提供可借鉴的研究方法与治疗思路。     

AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9

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Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures.     

Vaccination evokes gender-dependent protection against tularemia infection in C57BL/6Tac mice

Francisella tularensis (Ft) is a Category A biothreat agent for which there currently is no FDA-approved vaccine. Thus, there is a substantial effort underway to develop an effective tularemia vaccine. While it is well established that gender can significantly impact susceptibility to primary infection, the impact of gender on vaccine efficacy is not well established. Thus, development of a successful vaccine against tularemia will require an understanding of the impact gender has on vaccine-induced protection against this organism. In this study, a role for gender in vaccine-induced protection following Ft challenge is identified for the first time. In the present study, mucosal vaccination with inactivated Ft (iFt) LVS elicited gender-based protection in C57BL/6Tac mice against respiratory challenge with Ft LVS. Specifically, vaccinated male mice were more susceptible to subsequent Ft LVS challenge. This increased susceptibility in male mice correlated with increased bacterial burden, increased tissue inflammation, and increased proinflammatory cytokine production late in post-challenge infection. In contrast, improved survival of iFt-vaccinated female mice correlated with reduced bacterial burden and enhanced levels of Ft-specific Abs in serum and broncho-alveolar lavage (BAL) fluid post-challenge. Furthermore, vaccination with a live attenuated vaccine consisting of an Ft LVS superoxide dismutase (SodB) mutant, which has proven efficacious against the highly virulent Ft SchuS4 strain, demonstrated similar gender bias in protection post-Ft SchuS4 challenge. Of particular significance is the fact that these are the first studies to demonstrate that gender differences impact disease outcome in the case of lethal respiratory tularemia following mucosal vaccination. In addition, these studies further emphasize the fact that gender differences must be a serious consideration in any future tularemia vaccine development studies.