Pandemic Influenza H1N1 2009, Innate Immunity,and the Impact of Immunosenescence on Influenza Vaccine

Seasonal and pandemic strains of influenza have widespread implications for the global economy and global health. This has been highlighted recently as the epidemiologic characteristics for hospitalization and mortality for pandemic influenza H1N1 2009 are now emerging. While treatment with neuraminidase inhibitors are effective for seasonal and pandemic influenza, prevention of morbidity and mortality through effective vaccines requires a rigorous process of research and development. Vulnerable populations such as older adults (i.e., > age 65 years) suffer the greatest impact from seasonal influenza yet do not have a consistent seroprotective response to seasonal influenza vaccines due to a combination of factors. This short narrative review will highlight the emerging epidemiologic characteristics of pandemic H1N1 2009 and focus on immunosenescence, innate immune system responses to influenza virus infection and vaccination, and influenza vaccine responsiveness as it relates to seasonal and H1N1 pandemic influenza vaccines.     

Oral immunogenicity and protective efficacy in mice of transgenic rice plants producing a vaccine candidate antigen (As16) of Ascaris suum fused with cholera toxin B subunit

Cereal crops such as maize and rice are considered attractive for vaccine production and oral delivery. Here, we evaluated the rice Oryza sativa for production of As16—an antigen protective against the roundworm Ascaris suum. The antigen was produced as a chimeric protein fused with cholera toxin B subunit (CTB), and its expression level in the endosperm reached 50 μg/g seed. Feeding the transgenic (Tg) rice seeds to mice elicited an As16-specific serum antibody response when administered in combination with cholera toxin (CT) as the mucosal adjuvant. Although omitting the adjuvant from the vaccine formulation resulted in failure to develop the specific immune response, subcutaneous booster immunization with bacterially expressed As16 induced the antibody response, indicating priming capability of the Tg rice. Tg rice/CT-fed mice orally administered A. suum eggs had a lower lung worm burden than control mice. This suggests that the rice-delivered antigen functions as a prophylactic edible vaccine for controlling parasitic infection in animals.     

Opportunities and challenges with transitioning to non-lethal sampling of wild fish for microbiome research

The microbial communities of fish are considered an integral part of maintaining the overall health and fitness of their host. Research has shown that resident microbes reside on various mucosal surfaces, such as the gills, skin, and gastrointestinal tract, and play a key role in various host functions, including digestion, immunity, and disease resistance. A second, more transient group of microbes reside in the digesta, or feces, and are primarily influenced by environmental factors such as the host diet. The vast majority of fish microbiome research currently uses lethal sampling to analyse any one of these mucosal and/or digesta microbial communities. The present paper discusses the various opportunities that non-lethal microbiome sampling offers, as well as some inherent challenges, with the ultimate goal of creating a sound argument for future researchers to transition to non-lethal sampling of wild fish in microbiome research. Doing so will reduce animal welfare and population impacts on fish while creating novel opportunities to link host microbial communities to an individual's behavior and survival across space and time (e.g., life-stages, seasons). Current lethal sampling efforts constrain our ability to understand the mechanistic ecological consequences of variation in microbiome communities in the wild. Transitioning to non-lethal sampling will open new frontiers in ecological and microbial research.     

Identification of novel mimicry epitopes for cardiac myosin heavy chain-α that induce autoimmune myocarditis in A/J mice

Myocarditis is one cause of sudden cardiac death in young adolescents, and individuals affected with myocarditis can develop dilated cardiomyopathy, a frequent reason for heart transplantation. Exposure to environmental microbes has been suspected in the initiation of heart autoimmunity, but the direct causal link is lacking. We report here identification of novel mimicry epitopes that bear sequences similar to those in cardiac myosin heavy chain (MYHC)-α 334–352. These epitopes represent Bacillus spp., Magnetospirillum gryphiswaldense, Cryptococcus neoformans and Zea mays. The mimicry peptides induced varying degrees of myocarditis in A/J mice reminiscent of the disease induced with MYHC-α 334–352. We demonstrate that the mimics induce cross-reactive T cell responses for MYHC-α 334–352 as verified by MHC class II IA^k/tetramer staining and Th-1 and Th-17 cytokines similar to those of MYHC-α 334–352. The data suggest that exposure to environmental microbes which are otherwise innocuous can predispose to heart autoimmunity by molecular mimicry.     

Synthetic adjuvants for vaccine formulations: evaluation of new phytol derivatives in induction and persistence of specific immune response

Terpenoids are ubiquitous natural compounds that have been shown to improve vaccine efficacy as adjuvants. To gain an understanding of the structural features important for adjuvanticity, we studied compounds derived from a diterpene phytol and assessed their efficacy. In a previous report, we showed that phytol and one of its derivatives, PHIS-01 (a phytol-derived immunostimulant, phytanol), are excellent adjuvants. To determine the effects of varying the polar terminus of PHIS-01, we designed amine and mannose-terminated phytol derivatives (PHIS-02 and PHIS-03, respectively). We studied their relative efficacy as emulsions with soluble proteins, ovalbumin, and a hapten-protein conjugate phthalate-KLH. Immunological parameters evaluated consisted of specific antibody responses in terms of titers, specificities and isotype profiles, T cell involvement and cytokine production. Our results indicate that these new isoprenoids were safe adjuvants with the ability to significantly augment immunogen-specific IgG1 and IgG2a antibody responses. Moreover, there was no adverse phthalate cross-reactive anti-DNA response. Interestingly, PHIS-01 and PHIS-03 influenced differentially T-helper polarization. We also observed that these compounds modulated the immune response through apoptotic/necrotic effects on target tumor cells using murine lymphomas. Finally, unlike squalene and several other terpenoids reported to date, these phytol derivatives did not appear arthritogenic in murine models.     

An Integrin α4β7?IgG Heterodimeric Chimera Binds to MAdCAM-1 on High Endothelial Venules in Gut-Associated Lymphoid Tissue

Lymphocyte homing is regulated by a multistep process mediated by sequential adhesive interactions between circulating lymphocytes and high endothelial venules (HEVs). In gut-associated lymphoid tissue (GALT), the initial interactive step, “tethering and rolling,” is partly mediated by integrin α4β7 expressed on GALT-homing lymphocytes and its ligand MAdCAM-1, which is exclusively expressed on HEVs in GALT. To probe functional MAdCAM-1 in tissue sections, we developed a soluble integrin α4β7 heterodimeric IgG chimera by joining the extracellular region of mouse integrin α4 and β7 subunits to a human IgG Fc domain. Western blot analysis revealed that co-transfection of HEK 293T cells with expression vectors encoding integrin α4•IgG and β7•IgG results in the formation of α4β7•IgG heterodimeric chimeras. This complex preferentially binds to CHO cells expressing MAdCAM-1 and, to a lesser extent, to cells expressing VCAM-1, but not to cells expressing ICAM-1. Moreover, α4β7•IgG specifically binds to HEVs in GALT in situ in a divalent cation–dependent fashion and inhibits lymphocyte binding to HEVs in GALT. These findings indicate that α4β7•IgG can be used as a probe for functional MAdCAM-1 expressed on HEVs in GALT and could potentially serve as an anti-inflammatory drug inhibiting GALT-specific lymphocyte migration.     

从DNA疫苗到耐受疫苗:全新的适应症和抑炎前景

DNA疫苗技术从1990年代发现到至今,已经创造成功了4个临床兽用疫苗或产品,并仍然有数十个产品正在临床验证的不同阶段。通过不断提高DNA质粒进入体细胞的效率,DNA疫苗将具有更强的免疫应答效率,从而使得DNA疫苗走向更多和更广泛的临床应用。DNA疫苗不仅可以增强机体免疫系统的应答反应,利用其与蛋白质疫苗共免疫的方式也可以产生特异性的免疫耐受反应用于抑制免疫反应。基于DNA疫苗的诱导免疫耐受的疫苗技术开辟了全新的过敏性疾病和自主免疫疾病的干预领域,具有重要的临床潜力和应用前景。     

双歧杆菌乳杆菌三联活菌片对肝硬化自发性腹膜炎患者肠黏膜屏障功能的保护作用

目的探讨双歧杆菌乳杆菌三联活菌片对肝硬化自发性腹膜炎（SBP）患者肠黏膜屏障功能的保护作用。方法选取乙肝后肝硬化SBP患者68例,随机分为观察组和对照组各34例。两组患者均予以保肝利尿、降血氨、降低门脉压、抗感染、补充白蛋白和营养支持等常规治疗。观察组患者加用双歧杆菌乳杆菌三联活菌片2.0 g/次,2次/d,连用2周。对照组患者除不使用双歧杆菌乳杆菌三联活菌片余治疗同观察组。观察两组患者治疗前后血清DAO和D-Lac水平的变化,并比较临床疗效。结果治疗2周后,两组患者血清DAO和D-Lac水平均较前明显下降（P〈0.05或P〈0.01）,且观察组下降值明显大于对照组（P〈0.05）;同时观察组患者的临床总有效率（94.12%）明显高于对照组（73.53%）（χ2=5.31,P〈0.05）。结论双歧杆菌乳杆菌三联活菌片辅助治疗肝硬化SBP患者具有较好疗效,具有良好肠黏膜屏障保护功能。