Changes in antigen-specific T cell number and function during oral desensitization in cow’s milk allergy enabled with omalizumab

Food allergy is a major public health problem for which there is no effective treatment. We examined the immunological changes that occurred in a group of children with significant cow’s milk allergy undergoing a novel and rapid high dose oral desensitization protocol enabled by treatment with omalizumab (anti-IgE mAb). Within a week of treatment, the CD4+ T cell response to milk was nearly eliminated, suggesting anergy in, or deletion of, milk-specific CD4+ T cells. Over the following three months while the subjects remained on high doses of daily oral milk, the CD4+ T cell response returned, characterized by a shift from IL-4 to IFN-γ production. Desensitization was also associated with reduction in milk-specific IgE and a 15-fold increase in milk-specific IgG4. These studies suggest that high dose oral allergen desensitization may be associated with deletion of allergen-specific T cells, without the apparent development of allergen-specific Foxp3+ regulatory T cells

RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb–PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2–deficient mice showed that PD-L2 expression on non–T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events

Study of the role of interstitial macrophages in airway allergy

Respiratory mucosal surfaces are constantly exposed to a broad range of non-pathogenic environmental antigens. In the absence of proinflammatory signals, inhalation of harmless antigens results in immunological tolerance. Indeed, lung dendritic cells stimulate the development of antigen-specific regulatory T cells. Nevertheless, epidemiological studies have shown that ambient air contains not only inert antigens but also immunostimulatory molecules of microbial origin. Of particular interest are endotoxins, a cell wall component of gram-negative bacteria that is ubiquitous in the environment. In spite of the fact that high levels of endotoxin exposure in early life protect against allergic sensitization, most evidence indicates that exposure to house-dust endotoxin is a significant risk factor for increased asthma prevalence and severity. When the respiratory tract is stimulated with airborne endotoxins, lung dendritic cells lose their tolerogenic properties and rather promote the development of an allergic response directed against concomitant aeroantigens. Although endotoxins are omnipresent in the environment and favour airway allergy, only a minority of people develops asthma. A unifying model reconciling these conflicting observations is still lacking. We report here that LPS-triggered airway allergy is tightly controlled by lung interstitial macrophages, a cell population that remains largely uncharacterized. Interstitial macrophages could be distinguished from alveolar macrophages by their unique capacity to inhibit lung dendritic cell maturation and migration upon LPS stimulation, thereby preventing sensitization to concomitant inhaled antigens. We furthermore demonstrated that functional paralysis of LPS-stimulated dendritic cells involves interleukin-10 production by interstitial macrophages. Finally, we demonstrate that specific in vivo elimination of interstitial macrophages leads to overt asthmatic reactions to innocuous airborne antigens inhaled along with low LPS doses. Our study thus reveals a crucial role for interstitial macrophages in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that airborne LPS has the ability to promote the induction of Th2 responses by lung dendritic cells but does not provoke airway allergy under normal conditions. In the presence of LPS, interstitial macrophages, but not alveolar macrophages, break the link between innate and adaptive immunity, allowing harmless inhaled antigens to escape from T cell-dependent responses

IRF3 is required for the induction of allergic airway inflammation by lung dendritic cells in a mouse model of house dust mite-induced atopic asthma

peer reviewedaudience: researcher, professiona

Administration par inhalation de marbofloxacine chez le cheval: effets sur la fonction respiratoire - concentrations obtenues dans le liquide pulmonaire par rapport ) la voie IV

peer reviewe

Clinical effects of Carprofen during experimental bovine pneumonic mannheimiosis

peer reviewedM. haemolytica sérotype A1 (anciennement dénommée Pasteurella) est l’agent pathogène le plus fréquemment isolé lors de cas mortels de bronchopneumonie infectieuse bovine. M. haemolytica et ses deux principales toxines, le lipopolysaccharide (LPS) et la leucotoxine (LktA), induisent le recrutement, l’activation et la nécrose des neutrophiles fortement impliqués dans la pathogénie des broncho-pneumonies bovines à Mannheimia (BPM). Le but de notre étude fut de déterminer l’effet d’une administration thérapeutique de carprofène (Rimadyl® bovins*), un anti-inflammatoire non steroïdien (AINS), sur l’évolution des paramètres cliniques et nécropsiques dans un modèle de BPM aiguë expérimentalement induite chez des veaux. Les veaux ont été inoculés par M. haemolytica et ses toxines à T0, et traités (n=6) ou non (n=6) au caprofène (1,4 mg/kg IV) à T+1. Les paramètres cliniques et biochimiques ont été évalués une (T+1), trois (T+3) et sept (T+7) heures après inoculation. A T+1, l’établissement de la pathologie a été confirmée de manière significative par l’aggravation du score clinique et l’augmentation de la fréquence respiratoire chez l’ensemble des veaux. L’administration de carprofène a empêché une diminution de la saturation du sang en oxygène à T+3, une dégradation du score clinique et une augmentation de la lactatémie à T+7. Pour ces trois paramètres, les différences observées étaient significatives. Al’autopsie, l’étendue des lésions pulmonaires était diminuée de manière significative dans le groupe traité au carprofène. Ces résultats montrent que l’injection de carprofène après l’apparition des premiers signes cliniques de BPM permet d’améliorer l’état clinique des veaux et de réduire l’étendue des lésions pulmonaires.M. haemolytica serotype A1 (formerly known as Pasteurella) is the most important and commonly isolated bacterial pathogen from fatal cases of bovine fibrinous pleuroneumonia. M. haemolytica and its two principal toxins, the lipopolysaccharides (LPS) and the leukotoxin (LktA) induce the recruitment, the activation and the necrosis of neutrophils involved in the pathogenicity of bovine pneumonic mannheimiosis (BPM). The objective of this study was to determine whether systemic therapy with carprofène (Rimadyl®*), a non-steroidal anti-inflammatory drug, improves the disease development in an acute experimental model of BPM. The experimental pathology was induced by trans-tracheal inoculation of M. haemolytica and toxins at T0. One hour post-inoculation, six calves were treated intravenously with carprofen (1,4 mg/kg) while six placebo-treated calves received dose-matched volumes of sterile saline. The clinical and biochemical parameters were measured at one (T+1), three (T+3) and seven (T+7) hours after inoculation. Disease scores for carprofen treated calves were significantly lower than those for placebo-treated controls six hours (T+7) after treatment. These results were associated to a significantly oxygen saturation decrease at T+3 and a significantly blood lactate increase at T+7 in the control calves. Moreover, pulmonary lesions were significantly less extensive than those in the control group. Taken together, this finding suggest that pharmacological modulation by carprofen of pulmonary inflammation after appearance of acute BPM clinical signs leads to calves’ health enhancement and reduces the extent of gross pneumonic lesion