Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4+ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved

Successive influenza virus infection and Streptococcus pneumoniae stimulation alter human dendritic cell function

Background: Influenza virus is a major cause of respiratory disease worldwide and Streptococcus pneumoniae infection associated with influenza often leads to severe complications. Dendritic cells are key antigen presenting cells but its role in such co-infection is unclear.Methods: In this study, human monocyte derived-dentritic cells were either concurrently or successively challenged with the combination of live influenza virus and heat killed pneumococcus to mimic the viral pneumococcal infection. Dendritic cell viability, phenotypic maturation and cytokine production were then examined.Results: The challenge of influenza virus and pneumococcus altered dendritic cell functions dependent on the time interval between the successive challenge of influenza virus and pneumococcus, as well as the doses of pneumococcus. When dendritic cells were exposed to pneumococcus at 6 hr, but not 0 hr nor 24 hr after influenza virus infection, both virus and pneumococcus treated dendritic cells had greater cell apoptosis and expressed higher CD83 and CD86 than dendritic cells infected with influenza virus alone. Dendritic cells produced pro-inflammatory cytokines: TNF-α, IL-12 and IFN-γ synergistically to the successive viral and pneumococcal challenge. Whereas prior influenza virus infection suppressed the IL-10 response independent of the timing of the subsequent pneumococcal stimulation.Conclusions: Our results demonstrated that successive challenge of dendritic cells with influenza virus and pneumococcus resulted in synergistic up-regulation of pro-inflammatory cytokines with simultaneous down-regulation of anti-inflammatory cytokine, which may explain the immuno-pathogenesis of this important co-infection. © 2011 Wu et al; licensee BioMed Central Ltd.published_or_final_versio

Aktuelle Therapiekonzepte bei chronischer myeloischer Leukämie Die Studie IV der Deutschen CML-Studiengruppe

Zum Thema: Die chronische myeloische Leukämie (CML) stellt eine Modellerkrankung für Diagnostik und Therapie neoplastischer Erkrankungen dar. Die zu Grunde liegende zytogenetische Aberration, die Philadelphia-Translokation, mit der BCR-ABL-Genfusion sowie der mehrstufige Verlauf mit der stabilen, therapeutisch gut zu beeinflussenden chronischen Phase, der Akzelerationsphase und der Blastenphase ermöglichen die Übertragung molekularzytogenetischer Erkenntnisse in die klinisch-therapeutische Anwendung.Standardtherapien der CML sind Interferon-! (IFN) in Verbindung mit Hydroxyurea, sowie die allogene Stammzelltransplantation. Die Auswahl individuell geeigneter Therapien sollte unter Beachtung der modernen Risikoindices (IFN-Score und EBMT-Score) erfolgen. Eine Reduktion der Dosierung der Konditionierungstherapie ermöglicht die Stammzelltransplantation auch bei älteren Patienten. Auf der Grundlage der molekularen Aufklärung der Pathogenese der CML erfolgte die Entwicklung des selektiven Inhibitors der BCR-ABL-Tyrosinkinase Imatinib. Vielversprechende präklinische Daten wurden in Phase-I- bis -III-Studien bestätigt. Der Stellenwert der einzelnen Therapiebausteine wird im Rahmen der Studie IV der Deutschen CML-Studiengruppe geprüft

Postinfluenza Bacterial Pneumonia: Host Defenses Gone Awry

Influenza is a common respiratory pathogen causing both seasonal and pandemic disease. Influenza infection predisposes the host to secondary bacterial infection of the respiratory tract, which is a major cause of both morbidity and mortality in flu-related disease. In this review, we will discuss innate and adaptive antiviral responses during influenza infection, and review how these responses modulate protective immunity against secondary bacterial pathogens of the lung. Specific emphasis will be placed on implications of bacterial superinfection and mechanisms involved.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85106/1/jir_2010_0049.pd