Adult-Like Anti-Mycobacterial T Cell and In Vivo Dendritic Cell Responses Following Neonatal Immunization with Ag85B-ESAT-6 in the IC31® Adjuvant

BACKGROUND: With the exception of some live vaccines, e.g. BCG, subunit vaccines formulated with "classical" adjuvants do not induce similar responses in neonates as in adults. The usual neonatal profile is characterized by lower levels of TH1-associated biomarkers. This has hampered the development of new neonatal vaccines for diseases that require early protection. Tuberculosis is one of the major targets for neonatal immunization. In this study, we assessed the immunogenicity of a novel candidate vaccine comprising a mycobacterial fusion protein, Ag85B-ESAT-6, in a neonatal murine immunization model. METHODS/FINDINGS: The Ag85B-ESAT-6 fusion protein was formulated either with a classical alum based adjuvant or with the novel IC31 adjuvant. Following neonatal or adult immunization, 3 parameters were studied in vivo: (1) CD4(+) T cell responses, (2) vaccine targeting/activation of dendritic cells (DC) and (3) protection in a surrogate mycobacterial challenge model. Conversely to Alum, IC31 induced in both age groups strong Th1 and Th17 responses, characterized by multifunctional T cells expressing IL-2 and TNF-alpha with or without IFN-gamma. In the draining lymph nodes, a similarly small number of DC contained the adjuvant and/or the antigen following neonatal or adult immunization. Expression of CD40, CD80, CD86 and IL-12p40 production was focused on the minute adjuvant-bearing DC population. Again, DC targeting/activation was similar in adults and neonates. These DC/T cell responses resulted in an equivalent reduction of bacterial growth following infection with M. bovis BCG, whereas no protection was observed when Alum was used as adjuvant. CONCLUSION: Neonatal immunization with the IC31-adjuvanted Ag85B-ESAT-6 subunit vaccine elicited adult-like multifunctional protective anti-mycobacterial T cell responses through the induction of an adult pattern of in vivo DC activation

Multikomponenten-Darstellung staubbildender Sternhüllen

In den kühlen, ausgedehnten Hüllen weitentwickelter Sterne auf dem asymptotischen Riesenast (AGB) bilden sich kleine Festkörper. Dieser Staub führt durch den auf ihn wirkenden Strahlungsdruck zu einem massiven Materiestrom bzw. Wind. Eine realistische Beschreibung dieses aus vielen chemischen Komponenten bestehenden Materiestroms erfordert die konsistente Behandlung der Hydrodynamik, der Staubbildung, des Strahlungstransports und der Chemie der Gasphase aller am Wind beteiligten Komponenten. Das langfristige Ziel, das dieser Arbeit zu Grunde liegt, ist ein Mehrkomponenten-Hydrodynamik-Modell, das den Materiestrom sowohl der einzelnen unterschiedlichen Staub bildenden Moleküle, als auch das der daraus gebildeten Staubteilchen mit den unterschiedlichen Größen adäquat beschreibt. In dieser Arbeit wird ein Teilaspekt behandelt, der die Wechselwirkung zwischen der Gasphase und dem Staubanteil im betrachteten Materiestrom untersucht. An Hand eines stationären, sphärisch symmetrischen Modells wird in einem ersten Schritt das Verhalten des Gleichungsystems betrachtet. Die Wechselwirkungen der Staub- mit der Gasphase werden durch Austauschterme dargestellt, die sich aus der detaillierten Darstellung der hydrodynamischen Gleichungen ergeben. Es werden die speziellen Anforderungen und die daraus resultierenden Schwierigkeiten für die numerische Behandlung des erweiterten Gleichungssystems aufgezeigt.The outer regions of the cool, extended shells of evolved stars on the asymptotic giant branch (AGB) are the source of small grains. Driven by radiation, the newly formed dust leads to a massive outflow, respectively wind from the star. In order to model this outflow in a realistic way, a consistent description of hydrodynamics, dust formation, radiative transfer, and chemistry of the gas phase with all involved components is needed. In the long term, the basic goal consists in a multicomponent model of hydrodynamics including all dust-forming molecules as well as their successor dust particles with individual size and composition. The part of the project exploring the interac- tions between gas and dust in the outflow is subject matter of this work. Based on a stationary model in spherical symmetry, the behaviour of the underlying system of equations is studied. Interactions between the gas and the dust phase are introduced by coupling terms derived from the detailed elaboration of the hydrodynamic equations. The specific conditions and the resulting difficulties for the numerical treatment of the extended system of equations are discussed

Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma

BACKGROUND: The c-kit ligand, stem cell factor (SCF), is an important activating and chemotactic factor for both mast cells and eosinophils. These cells are known to play a fundamental role in the pathogenesis of asthma. OBJECTIVE: Our goal was to analyze the functional role of SCF in the pathogenesis of asthma. METHODS: The expression of SCF was targeted in fibroblasts, epithelial cells, and locally in a murine model of asthma in mice induced by ovalbumin sensitization with an antisense DNA strategy. RESULTS: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 epithelial cells by a specific antisense phosphorothioate oligonucleotide overlapping the translation start site of SCF, whereas control oligonucleotides were virtually inactive. We then focused on the role of SCF in a murine model of asthma associated with late-phase allergic inflammation in ovalbumin-sensitized mice: Local intranasal administration of FITC-labeled SCF antisense oligonucleotides led to strong DNA uptake in interstitial lung cells associated with a striking reduction of intracellular SCF expression. Such intrapulmonary blockade of SCF expression after repeated allergen challenges suppressed various signs of lung inflammation including IL-4 production and infiltration of eosinophils. SCF antisense DNA treatment was at least as effective as corticosteroid treatment. CONCLUSION: These data indicate a critical role for SCF in a murine asthma model and suggest that local delivery of SCF antisense oligonucleotides may be a novel approach for the treatment of inflammatory lung disorders such as asthma