Vaccinia‐based influenza vaccine overcomes previously induced immunodominance hierarchy for heterosubtypic protection

Growing concerns about unpredictable influenza pandemics require a broadly protective vaccine against diverse influenza strains. One of the promising approaches was a T cell‐based vaccine, but the narrow breadth of T‐cell immunity due to the immunodominance hierarchy established by previous influenza infection and efficacy against only mild challenge condition are important hurdles to overcome. To model T‐cell immunodominance hierarchy in humans in an experimental setting, influenza‐primed C57BL/6 mice were chosen and boosted with a mixture of vaccinia recombinants, individually expressing consensus sequences from avian, swine, and human isolates of influenza internal proteins. As determined by IFN‐γ ELISPOT and polyfunctional cytokine secretion, the vaccinia recombinants of influenza expanded the breadth of T‐cell responses to include subdominant and even minor epitopes. Vaccine groups were successfully protected against 100 LD₅₀ challenges with PR/8/34 and highly pathogenic avian influenza H5N1, which contained the identical dominant NP₃₆₆ epitope. Interestingly, in challenge with pandemic A/Cal/04/2009 containing mutations in the dominant epitope, only the group vaccinated with rVV‐NP + PA showed improved protection. Taken together, a vaccinia‐based influenza vaccine expressing conserved internal proteins improved the breadth of influenza‐specific T‐cell immunity and provided heterosubtypic protection against immunologically close as well as distant influenza strains.     

Acidic polysaccharide of Panax ginseng regulates the mitochondria/caspase-dependent apoptotic pathway in radiation-induced damage to the jejunum in mice

Owing to its susceptibility to radiation, the small intestine of mice is valuable for studying radioprotective effects. When exposed to radiation, intestinal crypt cells immediately go through apoptosis, which impairs swift differentiation necessary for the regeneration of intestinal villi. Our previous studies have elucidated that acidic polysaccharide of Panax ginseng (APG) protects the mouse small intestine from radiation-induced damage by lengthening villi with proliferation and repopulation of crypt cells. In the present study, we identified the molecular mechanism involved. C57BL/6 mice were irradiated with gamma-rays with or without APG and the expression levels of apoptosis-related molecules in the jejunum were investigated using immunohistochemistry. APG pretreatment strongly decreased the radiation-induced apoptosis in the jejunum. It increased the expression levels of anti-apoptotic proteins (Bcl-2 and Bcl-X_S/L) and dramatically reduced the expression levels of pro-apoptotic proteins (p53, BAX, cytochrome c and caspase-3). Therefore, APG attenuated the apoptosis through the intrinsic pathway, which is controlled by p53 and Bcl-2 family members. Results presented in this study suggest that APG protects the mouse small intestine from irradiation-induced apoptosis through inhibition of the p53-dependent pathway and the mitochondria/caspase pathway. Thus, APG may be a potential agent for preventing radiation induced injuries in intestinal cells during radio-therapy such as in cancer treatment.     

Trends and risk factors of elderly-onset Crohn's disease: A nationwide cohort study

BACKGROUND The incidence of inflammatory bowel disease(IBD)is increasing in Asia.Numerous risk factors associated with IBD development have been investigated.AIM To investigate trends and environmental risk factors of Crohn’s disease(CD)diagnosed in persons aged≥40 years in South Korea.METHODS Using the National Health Insurance Service database,a total of 14060821 persons aged>40 years who underwent national health screening in 2009 were followed up until December 2017.Patients with newly diagnosed CD were enrolled and compared with non-CD cohort.CD was identified according to the International Classification of Diseases 10th revision and the rare/intractable disease registration program codes from the National Health Insurance Service database.The mean follow-up periods was 7.39 years.Age,sex,diabetes,hypertension,smoking,alcohol consumption,regular exercise,body mass index,anemia,chronic kidney disease(CKD)and dyslipidemia were adjusted for in the multivariate analysis model.RESULTS During the follow-up,1337(1.33/100000)patients developed CD.Men in the middle-aged group(40-64 years)had a higher risk than women[adjusted hazard ratio(aHR)1.46,95%confidence interval(CI):1.29-1.66];however,this difference tended to disappear as the age of onset increases.In the middle-aged group,patients with a history of smoking[(aHR 1.46,95%CI:1.19-1.79)and anemia(aHR 1.85,95%CI:1.55-2.20)]had a significantly higher CD risk.In the elderly group(age,≥65 years),ex-smoking and anemia also increased the CD risk(aHR 1.68,95%CI:1.22-2.30)and 1.84(95%CI:1.47-2.30,respectively).Especially in the middle-aged group,those with CKD had a statistically elevated CD risk(aHR 1.37,95%CI:1.05-1.79).Alcohol consumption and higher body mass index showed negative association trend with CD incidence in both of the age groups.[Middle-aged:aHR 0.77(95%CI:0.66-0.89)and aHR 0.73(95% CI:0.63-0.84),respectively][Elderly-group:aHR 0.57(95% CI:0.42-0.78)and aHR 0.84(95%CI 0.67-1.04),respectively].For regular physical activity and dyslipidemia,negative correlation between CD incidences was proved only in the middle-aged group[aHR 0.88(95%CI:0.77-0.89)and aHR 0.81(95%CI:0.68-0.96),respectively].CONCLUSION History of cigarette smoking,anemia,underweight and CKD are possible risk factors for CD in Asians aged>40 years.     

Fusion of Na-ASP-2 with human immunoglobulin Fcγ abrogates histamine release from basophils sensitized with anti-Na-ASP-2 IgE

Na-ASP-2 is a major protein secreted by infective third-stage larvae (L3) of the human hookworm Necator americanus upon host entry. It was chosen as a lead vaccine candidate for its ability to elicit protective immune responses. However, clinical development of this antigen as a recombinant vaccine was halted because it caused allergic reactions among some of human volunteers previously infected with N.?americanus. To prevent IgE-mediated allergic reactions induced by Na-ASP-2 but keep its immunogenicity as a vaccine antigen, we designed and tested a genetically engineered fusion protein, Fcγ/Na-ASP-2, composed of full-length Na-ASP-2 and truncated human IgG Fcγ1 that targets the negative signalling receptor FcγRIIb expressed on pro-allergic cells. The chimeric recombinant Fcγ/Na-ASP-2 protein was expressed in Pichia pastoris and shared the similar antigenicity as native Na-ASP-2. Compared to Na-ASP-2, the chimeric fusion protein efficiently reduced the release of histamine in human basophils sensitized with anti-Na-ASP-2 IgE obtained from individuals living in a hookworm-endemic area. In dogs infected with canine hookworm, Fcγ/Na-ASP-2 resulted in significantly reduced immediate-type skin reactivity when injected intradermally compared with Na-ASP-2. Hamsters vaccinated with Fcγ/Na-ASP-2 formulated with Alhydrogel(?) produced specific IgG that recognized Na-ASP-2 and elicited similar protection level against N.?americanus L3 challenge as native Na-ASP-2.     

Effect of humoral factors from hPDLSCs on the biologic activity of hABCs

Oral Diseases (2012) 18, 537–547 Objective: The human periodontal ligament stem cells (hPDLSCs) and human alveolar bone–derived stromal cells (hABCs) seem to be closely involved in the maintenance of alveolar bone in an anatomically indirect manner; however, there is little study on this matter. Therefore, the effect of hPDLSCs on the osteoclastogenic, osteogenic, and adipogenic differentiation of hABCs was evaluated, focusing on the humoral factors released by hPDLSCs. Materials and methods: Human periodontal ligament stem cells and hABCs were isolated and characterized. hPDLSCs were indirectly cocultured to observe the in vitro effect of humoral factors released from hPDLSCs on the osteoclastogenic, osteogenic, and adipogenic differentiation of hABCs. Human gingival fibroblasts (hGFs) were utilized as positive control. Results: Isolated cells demonstrated the presence of stem cells within. Indirect coculture of hPDLSCs greatly inhibited osteoclastogenesis by hABCs. Osteogenesis/adipogenesis of hABCs was also inhibited by indirect coculture with hPDLSC. The magnitude of regulatory effect from hPDLSCs was significantly greater than that of hGFs. Conclusions: Humoral factors released from hPDLSCs seemed to modulate the differentiation of hABCs, and the osteoclastogenic, osteogenic, and adipogenic differentiation of hABCs was all inhibited, suggesting the potential role of hPDLSCs in the maintenance of the alveolar bone.     

Fusobacterium nucleatum GroEL induces risk factors of atherosclerosis in human microvascular endothelial cells and ApoE(-/-) mice

Infection and inflammation are risk factors in the initiation and progression of atherosclerosis. Periodontitis is one of the most prevalent chronic inflammations of the oral cavity, and has been reported to be associated with systemic disease. In this study, we evaluated whether the heat-shock protein GroEL of Fusobacterium nucleatum, one of the most prevalent bacteria in periodontitis, induces factors that predispose to atherosclerosis in human microvascular endothelial cells (HMEC-1) and apolipoprotein E-deficient (ApoE(-/-)) mice. GroEL induced the expression of chemokines such as monocyte chemoattractant protein-1 and interleukin-8 as well as cell adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. GroEL induced the activity of tissue factor and reduced the activity of the tissue factor pathway inhibitor. Foam cell formation was induced by GroEL. GroEL-injected ApoE(-/-) mice showed significant atherosclerotic lesion progression compared with control mice. Serum levels of risk factors for atherosclerosis such as interleukin-6, C-reactive protein, and low-density lipoprotein were increased in GroEL-injected ApoE(-/-) mice compared with control mice, whereas serum levels of high-density lipoprotein were decreased. We could detect significantly higher levels of anti-F. nucleatum GroEL antibody in serum and F. nucleatum DNA in gingival crevicular fluid from patients with periodontitis than in that from healthy subjects. Our results indicate that the host response to the GroEL of periodontal pathogens like F. nucleatum may be a mechanism involved in atherosclerosis, supporting the association of periodontitis and systemic infection.