C5aR1 Activation Drives Early IFN-gamma Production to Control ExperimentalToxoplasma gondiiInfection

Toxoplasma gondii (T. gondii) is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) senseT. gondiithrough TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-gamma as an essential mechanism for early parasite control. Further, C3 can bind toT. gondiiresulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritonealT. gondiiinfection. We found thatC5ar1(-/-)animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection inC5ar1(-/-)mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-gamma. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1 alpha, IL-6, and TNF-alpha, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-gamma production was associated with diminishedIfngmRNA expression in the spleen and the brain, reduced frequency of IFN-gamma+NK cells in the spleen, and decreasedNos2expression in the brain ofC5ar1(-/-)mice. Mechanistically, DCs from the spleen ofC5ar1(-/-)mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulationin vivoandin vitro. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-gamma production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acuteT. gondiiinfection

Angeborene Fehlbildungen der Lunge – eine Übersicht

Kongenitale pulmonale Malformationen stellen eine heterogene Gruppe seltener Erkrankungen dar, die auf Fehlentwicklungen während der embryonalen und fetalen Wachstumsphase basieren. Zu ihnen gehören der Trachealbronchus, die bronchiale Atresie, die bronchogene Zyste, die Lungensequestration, das kongenitale lobäre Emphysem sowie die sogenannte Congenital pulmonary Airway Malformation. Eines der Leitsymptome dieser Malformationen ist die durch ihren verdrängenden Effekt bedingte postnatale respiratorische Insuffizienz, welche eine rasche operative Versorgung erfordert. Auch bei asymptomatischen Malformationen wird aufgrund des erhöhten Infektrisikos die Resektion empfohlen. In der folgenden Übersicht wird auf die Ursachen, das klinische Bild und die therapeutischen Optionen dieser angeborenen Fehlbildungen der Lunge und des Bronchialsystems eingegangen. = Congenital pulmonary malformations comprise a heterogenous group of rare developmental diseases. The most common malformations are the tracheal bronchus, bronchial atresia, bronchogenic cyst, pulmonary sequestration, congenital lobar emphysema, and congenital pulmonary airway malformation. Due to their space-consuming effect, patients suffer early postnatal respiratory distress which generally requires immediate surgical resection. The management of asymptomatic lesions remains subject to debate, but early elective surgery is generally recommended to avoid respiratory and infectious complications at a later time point.We here provide a comprehensive review in which we present causes, clinical presentation and therapeutic options for the most prominent congenital malformations of the airways and lung parenchyma

Balancing the Risk of Adverse Events against the Efficacy of Immunotherapy in Advanced Thymic Epithelial Tumors

Thymic epithelial tumors (TETs) are rare thoracic malignancies with a favorable prognosis when complete surgical resection can be achieved. Therapeutic options for advanced, irresectable, or recurrent disease are limited and currently, a therapeutic standard treatment beyond platinum-based chemotherapy is undefined. Immune checkpoint inhibitors are effective against TETs, however their use is associated with a serious risk of immune-mediated toxicity. In this article, we highlight new insights regarding markers of predictive value for both treatment efficacy and risk of adverse effects in immune checkpoint inhibitor treatment for thymic epithelial tumors

B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications

Allograft rejection remains the major hurdle in lung transplantation despite modern immunosuppressive treatment. As part of the alloreactive process, B cells are increasingly recognized as modulators of alloimmunity and initiators of a donor-specific humoral response. In chronically rejected lung allografts, B cells contribute to the formation of tertiary lymphoid structures and promote local alloimmune responses. However, B cells are functionally heterogeneous and some B cell subsets may promote alloimmune tolerance. In this review, we describe the current understanding of B-cell-dependent mechanisms in pulmonary allograft rejection and highlight promising future strategies that employ B cell-targeted therapies

Balancing the Risk of Adverse Events against the Efficacy of Immunotherapy in Advanced Thymic Epithelial Tumors

Thymic epithelial tumors (TETs) are rare thoracic malignancies with a favorable prognosis when complete surgical resection can be achieved. Therapeutic options for advanced, irresectable, or recurrent disease are limited and currently, a therapeutic standard treatment beyond platinum-based chemotherapy is undefined. Immune checkpoint inhibitors are effective against TETs, however their use is associated with a serious risk of immune-mediated toxicity. In this article, we highlight new insights regarding markers of predictive value for both treatment efficacy and risk of adverse effects in immune checkpoint inhibitor treatment for thymic epithelial tumors

Neue Entwicklungen in der Immuntherapie fortgeschrittener epithelialer Thymustumoren

Epitheliale Thymustumoren sind seltene thorakale Tumoren des vorderen Mediastinums, deren Prognose primär von einer vollständigen chirurgischen Resektion und ihrem histologischen Subtyp abhängig ist. Die therapeutischen Optionen in fortgeschrittenen, nicht operablen Tumorstadien sind begrenzt. Über eine Platin-basierte Chemotherapie hinaus gibt es keinen definierten therapeutischen Standard. Der Einsatz von Immuntherapeutika kann hier einen vielversprechenden Ansatz darstellen, ist jedoch bei Thymustumoren mit erhöhten Nebenwirkungsraten verbunden. Aktuell werden Kombinationstherapien von Immuncheckpoint-Inhibitoren (ICIs) mit antiangiogenen Substanzen in klinischen Studien evaluiert

Balancing the Risk of Adverse Events against the Efficacy of Immunotherapy in Advanced Thymic Epithelial Tumors

Thymic epithelial tumors (TETs) are rare thoracic malignancies with a favorable prognosis when complete surgical resection can be achieved. Therapeutic options for advanced, irresectable, or recurrent disease are limited and currently, a therapeutic standard treatment beyond platinum-based chemotherapy is undefined. Immune checkpoint inhibitors are effective against TETs, however their use is associated with a serious risk of immune-mediated toxicity. In this article, we highlight new insights regarding markers of predictive value for both treatment efficacy and risk of adverse effects in immune checkpoint inhibitor treatment for thymic epithelial tumors

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis