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Resume Apparue au debut du xx e siecle, l’immunotherapie specifique des allergenes (ITS) a ete largement utilisee dans la rhinite et l’asthme allergique et dans l’allergie au venin d’hymenopteres sans connaitre precisement ses mecanismes d’action. Cependant, le developpement des outils de l’immunologie moderne a permis de faire d’importantes avancees sur ces mecanismes qui, une fois completement compris, permettront d’envisager de nouvelles strategies d’ITS. On considere actuellement que l’ITS modifie la reponse immune vis-a-vis des allergenes en induisant une reorientation de la reaction inflammatoire dans un sens Th1 et T regulateur, avec induction de la production d’IFN-gamma et d’interleukine-10. Cette action s’exerce a la fois au niveau de l’immunite adaptative (cellules T) et de l’immunite innee (cellules presentatrices d’allergene).

There is no unequivocal definition of exacerbation in asthma. These are defined as episodes of increased or aggravated respiratory symptoms or as use of oral corticosteroid therapy. Viral infection is the most frequent cause of exacerbations. Inflammation during exacerbations is heterogeneous. It may be associated with bronchial hypereosinophilia, which is used as a predictive marker for exacerbation, and with neutrophilia, which is more resistant to corticosteroids. During viral infection, an inappropriate Th1 antiviral inflammation develops, associated with the intrinsic Th2 activity that leads to an aberrant immune response. Exacerbations secondary to allergen exposure are classically described as due to a Th2-type inflammation; but Th1 response also seems to play a role. Exposure to air pollutants appears able not only to induce bronchial inflammation but also to potentiate the inflammatory reactions of patients with exacerbations.

Resume Les lymphocytes T CD8+ recouvrent une diversite de populations lymphocytaires T aux fonctions variees : CD8+ αβ, producteurs de cytokines (Tc1, Tc2), cytotoxiques, CD8+ NKT, CD8+ γδ. Leur role a ete explore dans l’asthme dans un nombre limite de travaux repris dans cette revue. Selon les modeles animaux, les lymphocytes T conventionnels CD8+ αβ sont protecteurs ou amplificateurs vis-a-vis de la reaction immuno-allergique. Si les Tc2 sont toujours amplificateurs, le role des Tc1 est controverse. Les lymphocytes T cytotoxiques producteurs de perforine et CX3CR1+ sont retrouves en exces chez les asthmatiques, notamment lors des exacerbations. L’infiltration bronchique par les lymphocytes T CD8+ est liee dans l’asthme au declin du VEMS, comme dans la BPCO. De plus, elle est liee a la mortalite par asthme. Au cours des exacerbations, les virus, les allergenes et/ou les polluants induisent des lymphocytes T CD8+ capables d’augmenter l’inflammation de l’asthmatique, probablement de facon non specifique, via la participation de lymphocytes T CD8+ spectateurs. Le role des lymphocytes T non conventionnels γδ est egalement controverse selon les modeles. Ces lymphocytes intermediaires entre l’immunite innee et l’immunite adaptative, qui reconnaissent des antigenes non peptidiques, sont impliques notamment dans l’asthme professionnel aux agents de bas poids moleculaire. En conclusion, toutes les populations de lymphocytes T CD8+ sont impliquees dans l’inflammation de l’asthmatique. Elles sont liees aux exacerbations et a la severite de l’asthme. Leur activation est moins sensible aux corticoides que celle des lymphocytes T CD4+. C’est ainsi que le ciblage des lymphocytes T apparait comme une piste therapeutique importante dans l’asthme severe cortico-dependant.

Introduction: CLAD and its phenotypes, Bronchiolitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS) are major causes of mortality after lung transplantation (LT). Aims: To identify clinical factors associated with stable allograft function, BOS or RAS in the French and Swiss LT cohorts (SysCLAD cohort). Methods: Patients who completed a 3-year follow-up, died or had a 2 nd LT within 3 years were included in the study. An audit group of LT specialists assessed pulmonary function tests, chest CT scans and confounding factors to identify stable patients, RAS and BOS. Recipient and donor baseline characteristics, data on surgery, immunosuppressive treatment, follow-up events and outcomes were collected. Logistic regression analysis (LRA) was used for predictors of CLAD and multivariate multinomial analysis (MMA) for predictors of BOS, RAS and stability. Results: The SysCLAD cohort included 422 patients, 19% of whom had CLAD (BOS n=51, RAS n=31), 35% were stable, 10% had an inconclusive CLAD phenotype due to the presence of confounding factors and 36% died or underwent a 2 nd LT not due to CLAD. Factors positively associated with CLAD in the LRA were thymoglobulin use and the number of treated infections during year 1. In MMA, thymoglobulin induction was associated with BOS, the number of treated infections by year 1 was associated with RAS, the presence of de novo donor-specific antibodies was associated with BOS and RAS while stability was associated with the diagnosis of cystic fibrosis. Conclusion: Clinical factors such as thymoglobulin use or infections early after LT may assist to predict stability, BOS or RAS. Their identification may allow intervention or guide risk stratification.

We studied the role of chronic exposure to ambiant air pollution on lung function level and evolution in lung transplant patients. The lung function of 525 lung transplant (LT) patients from the COLT cohort was followed-up. The 12-month average levels of air pollutants (Nitrogen dioxide (NO 2 ), fine particulate matters (PM 2.5 , PM 10 ) and ozone (O 3 )) were estimated at the home addresses of each patient. The effect of air pollutant exposure on FEV 1 level and change in FEV 1 both during the recovery and decline periodes were estimated using mixed linear regression models adjusted on recipient age, sex, smoking (donor and patient), body mass index, donor age, type of LT, underlying disease, sex and HLA mismatch, ischemia time, anti-HLA antibodies, Pseudomonas colonization, CMV infections, immunosuppression induction and acute rejection. The population included 54% of men and 81% of double LT (mean age 43yrs). The main underlying diseases were cystic fibrosis (40%), emphysema/COPD (34%) and pulmonary arterial hypertension (14%). Mean (sd) individual exposure levels were 15.2 (2.1), 22.1 (3.1), 18.1 (7.3) and 51.7 (8.2) µg/m 3 for PM 2.5 , PM 10 , NO 2 and O 3 , respectively. NO 2 exposure was significantly associated with lower FEV 1 levels measured during the recovery period and a non-significant trend was observed in the decline period (estimate (se) = -3.39(1.48) p=0.02 and -1.96(1.47) p=0.18). None of the air pollutants exposure was associated with change in FEV 1 . Our results suggest a potential deleterious effect of chronic exposure to NO 2 on FEV 1 level following LT and did not evidence an effect of air pollution on change in FEV 1 . Fundings: EU-FP7 SYSCLAD, Vaincre la Mucoviscidose, Association Gregory Lemarchal.

Resume L'asthme severe represente une entite heterogene dont l'immunopathologie est mal connue du fait de la difficulte d'obtenir du materiel in situ chez ces patients. Il existe deux types d'asthmes severes en fonction de la presence ou non d'eosinophiles. Les asthmes severes avec eosinophilie de debut precoce ont une physiopathologie proche de celle des asthmes moins severes, avec une infiltration Th2. Ils sont plus a meme de developper des exacerbations. De debut tardif, ces asthmes sont plus proches des syndromes hypereosinophiliques. Les asthmes severes sans eosinophilie sont le plus souvent le siege d'une infiltration a neutrophiles. Ce sont ceux qui repondent le moins aux corticoides. L'expectoration induite permet un suivi longitudinal non invasif de l'inflammation bronchique dans l'asthme severe, permettant d'obtenir une comparaison de l'activation cellulaire pendant les exacerbations et en dehors. L'etude ISEA (Induced Sputum in Exacerbations of Asthma) a ainsi permis de montrer qu'au cours des exacerbations, on observe une activation simultanee des lymphocytes Th1 et Th2 et un deficit accentue en lymphocytes T regulateurs. Ce type d'approche est essentiel, dans le but d'identifier des cibles therapeutiques pertinentes, et aussi eventuellement de detecter des marqueurs precoces predictifs des exacerbations.

Resume Etat des connaissances L’inflammation allergique est consideree comme le resultat d’une activation des lymphocytes Th2. Pourtant cette inflammation, pertinente pour l’atopie et la presence des eosinophiles dans les tissus atteints, est insuffisante pour expliquer l’asthme. Plusieurs travaux ont montre qu’a l’inflammation de type Th2, etait associee dans l’asthme une inflammation Th1 avec production d’IFN-gamma. Par ailleurs il a ete montre recemment que des lymphocytes T dits regulateurs (Treg), producteurs d’IL-10 et/ou de TGF-beta et inducteurs de tolerance etaient deficitaires chez les sujets allergiques. De plus, ces lymphocytes augmentent lors de l’immunotherapie specifique. Leur diminution pourrait rendre compte de l’activation Th2 rencontree chez l’atopique. Perspectives Dans cette courte revue, nous faisons le point sur l’importance potentielle des Treg dans l’atopie et l’asthme. Nous proposons un concept selon lequel la reaction inflammatoire allergique ne repose pas sur la rupture d’une balance Th1/Th2 mais sur un deficit en Treg. Ce deficit serait progressivement croissant du sujet normal a l’atopique, de l’atopie a l’asthme et de l’asthme a l’exacerbation. Conclusion Trois dimensions de l’inflammation sont alors a prendre en compte : Th1, Th2, Treg.

International audience; Airway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype. These cells are then able to migrate and secrete ECM molecules. Herein, we review the different types of EMT. We will then focus on the signalling pathways that are involved, such as transforming growth factor-b and Wnt, as well as the more recently described Sonic Hedgehog pathway. Finally, we will highlight the implication of EMT in airway remodelling in specific chronic bronchial pathologies, such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans following lung transplantation. Despite the limitations of in vitro models, future studies of EMT in vivo are warranted to shed new light on the pathomechanisms of bronchial obstruction.

Background Th2 cell activation and T regulatory cell (Treg) deficiency are key features of allergy. This applies for asthma and rhinitis. However with a same atopic background, some patients will develop rhinitis and asthma, whereas others will display rhinitis only. Co-receptors are pivotal in determining the type of T cell activation, but their role in allergic asthma and rhinitis has not been explored. Our objective was to assess whether allergen-induced T cell activation differs from allergic rhinitis to allergic rhinitis with asthma, and explore the role of ICOS, CD28 and CTLA-4. Methods T cell co-receptor and cytokine expressions were assessed by flow cytometry in PBMC from 18 house dust mite (HDM) allergic rhinitics (R), 18 HDM allergic rhinitics and asthmatics (AR), 13 non allergic asthmatics (A) and 20 controls, with or without anti-co-receptors antibodies. Results In asthmatics (A+AR), a constitutive decrease of CTLA-4+ and of CD4+CD25+Foxp3+ cells was found, with an increase of IFN-γ+ cells. In allergic subjects (R + AR), allergen stimulation induced CD28 together with IL-4 and IL-13, and decreased the proportion of CTLA-4+, IL-10+ and CD4+CD25+Foxp3+ cells. Anti-ICOS and anti-CD28 antibodies blocked allergen-induced IL-4 and IL-13. IL-13 production also involved CTLA-4. Conclusions T cell activation differs between allergic rhinitis and asthma. In asthma, a constitutive, co-receptor independent, Th1 activation and Treg deficiency is found. In allergic rhinitis, an allergen-induced Treg cell deficiency is seen, as well as an ICOS-, CD28- and CTLA-4-dependent Th2 activation. Allergic asthmatics display both characteristics.

Exacerbations of asthma are the main cause of asthma morbidity. They induce acute respiratory failure, and sometimes death. Two immunological signals acting in synergy are necessary for inducing asthma exacerbations. The first, triggered by allergens and/or unknown agents leads to the chronic Th2 inflammation characteristic of asthma. The second, caused by either viral infection, allergens, pollutants or a combination of these, results in an acute Th1 and Th2 inflammation precipitating symptoms. In both, innate and adaptive immunities are involved, providing a series of potential targets for therapy. Molecules associated to the first, chronic inflammation constitute targets for preventing therapies, when these related to the second, acute signal provide the rationale for curative treatments. Toll like receptors and bronchial epithelial cell-derived cytokines, engaged upstream of inflammation constitute interesting candidates for future treatments. The great heterogeneity of asthma has to be taken into account when considering targets for therapy to identify clusters of responders and nonresponders, and an integrative system biology approach will be necessary to go further.

Exacerbations represent a major clinical issue in asthma management, leading to hospitalizations, acute respiratory failure and sometimes death. They induce the main costs of asthma management in terms of care recourse and loss of working days. Their mechanisms must be carefully elucidated to design new drugs able to prevent them. Exacerbations are mainly caused by viral infection, and also allergen and pollutant exposure. These triggers induce exacerbations in asthmatic subjects already displaying a chronic bronchial inflammation caused itself by allergy, pollutants and/or perhaps infection. Exacerbations therefore result from two additive immunological signals. Both signals involve innate immunity via the activation of epithelial and dendritic cells. The first signal induces chronic epithelium damage and activation. By stimulating cytokine production and coreceptors expression by dendritic cells, it determines the type of inflammatory response leading to T cell activation and polymorphonuclear cells homing and activation. The second signal acutely enhances the chronic inflammation and eventually adds a distinct type of inflammation to the first chronic response. These mechanisms will be discussed in the context of the various triggers involved, both from an epidemiologic and immunologic point of view.

Summary Background Effects of mast cell-released histamine on smooth muscle and endothelial cells are considered as responsible of immediate symptoms of anaphylaxis. However, little is known about histamine effects on Th2 lymphocytes, which orchestrate the allergic reaction upstream of mast cells. Objective We addressed this question in house dust mite (HDM) allergics, according to the presence of rhinitis or asthma and allergen stimulation. Methods Peripheral blood mononuclear cell from 15 rhinitic and 14 asthmatic HDM-allergic subjects and 16 controls were cultured with Der p 1 or histamine. The effect of Der p 1 on histamine receptor (H1R and H2R) expression was studied. T-cell cytokine production was studied upon Der p 1 or histamine stimulation. The role of H1R in histamine effects was assessed with levocetirizine. Results H1R and H2R are overexpressed on T cells from asthmatic but not from rhinitic subjects. Der p 1 increases H1R expression on CD4+ cells from both allergic groups, and decreases it in controls, on CD4+ and CD8+ subsets. Der p 1 decreases T-cell H2R expression in asthmatics. Allergen increases IL-4 and IL-13 in both allergic groups. Histamine increases Th2 cytokines in rhinitics only, and levocetirizine abolishes this effect. In asthmatics and controls, histamine decreases T-cell cytokines through a non-H1R dependent pathway. Conclusion In rhinitis but not in asthma, histamine is able to increase allergic inflammation by increasing Th2 cytokine production in a positive feedback dependent on H1R. This result could explain in part why H1R antagonists, are very efficient in rhinitis, but not in asthma. Cite this as: K. Botturi, Y. Lacoeuille, D. Vervloet and A. Magnan, Clinical & Experimental Allergy, 2010 (40) 755–762.

Summary Appeared at the beginning of the 20th century, allergen-specific immunotherapy (SIT) has long been used in allergic rhinitis and asthma without any knowledge of its mechanisms of action or any tangible proof of its efficacy. However, from the beginning of the era of evidence-based medicine, a number of placebo-controlled studies have been published and reached a sufficient number to assess the cellular events induced by SIT and allow meta-analysis to provide guidelines based on proofs. Controlled studies and meta-analysis concerned not only subcutaneous immunotherapy but also the sublingual route, demonstrating an effect of SIT on symptoms and medication use. Most recently sublingual tablets were proposed in allergic rhinitis. This paper reviews the mechanisms of SIT, the evidence of efficacy of SIT from the injective to the sublingual route and reminds the current guidelines.

There is no unequivocal definition of exacerbation in asthma. These are defined as episodes of increased or aggravated respiratory symptoms or as use of oral corticosteroid therapy. Viral infection is the most frequent cause of exacerbations. Inflammation during exacerbations is heterogeneous. It may be associated with bronchial hypereosinophilia, which is used as a predictive marker for exacerbation, and with neutrophilia, which is more resistant to corticosteroids. During viral infection, an inappropriate Th1 antiviral inflammation develops, associated with the intrinsic Th2 activity that leads to an aberrant immune response. Exacerbations secondary to allergen exposure are classically described as due to a Th2-type inflammation; but Th1 response also seems to play a role. Exposure to air pollutants appears able not only to induce bronchial inflammation but also to potentiate the inflammatory reactions of patients with exacerbations.

Immune characteristics distinguishing tolerant lung transplant recipients (LTR) from patients with Bronchiolitis obliterans syndrome (BOS) are largely unknown. We compared the effect of dendritic cells (DC) on T-cell activation in healthy LTR (non BOS) and in BOS patients. 30 Non BOS and 14 BOS recipients were studied. Mature dendritic cells were derived from blood monocytes and co-cultured with autologous T cells at various ratios. T cell CD69, CD25, CD28, ICOS and CTLA-4 expression and IL-4, IL-13, IFN-, and IL-10 production were assessed by flow cytometry. Dendritic cell expression of surface markers and indoleamine 2,3 dioxygenase was also studied. Experiments were repeated in presence of P. aeruginosa or anti-CTLA-4 antibodies. In dendritic cell/LT co-cultures, T cell CD69, CD28 and ICOS decreased in non BOS (p

L'asthme est une maladie inflammatoire heterogene caracterisee par de multiples phenotypes cliniques et inflammatoires. Dans ce travail de these, nous avons pu mettre en avant l'implication de la reponse lymphocytaire T auxiliaire 17 (TH17) dans deux composantes majeures de l'asthme: la contraction bronchique et l'inflammation pulmonaire. Dans un premier temps, nous avons caracterise notre modele murin d'asthme allergique aux acariens sur le plan fonctionnel et inflammatoire. Le mode de sensibilisation allergique par voie cutanee puis respiratoire est responsable de l'induction d'un phenotype inflammatoire mixte : en plus d'une hyperreactivite bronchique, les souris « asthmatiques » presentent un important infiltrat inflammatoire a neutrophiles et eosinophiles. Cet l'infiltrat pulmonaire est correle a de fortes reponses TH2 et TH17 avec production d'IL-13, d'IL-4 et d'IL-17A. Dans un deuxieme temps, nous avons etudie la contribution individuelle de l'IL-17A et de l'IL-13 dans notre modele. Nous constatons que l'IL-17A mais pas l'IL-13 est responsable de l'infiltrat a neutrophiles et de l'hyperreactivite bronchique. Bien que les neutrophiles ont un role important dans la reponse contractile, nos resultats ont mis en evidence un role direct de l'IL-17A sur le muscle lisse. Ce mecanisme de regulation induit par l'IL-17 est dependant de l'activite d'une petite proteine G, appelee Rac 1. Nos resultats decrivent un role majeur de l'IL-17A dans un asthme a inflammation mixte. La neutralisation de cette cytokine peut reduire non seulement l'inflammation pulmonaire mais aussi la contraction bronchique. L'IL-17A represente une cible therapeutique potentielle dans les asthmes severes.

Introduction Bien que de considerables progres aient ete realises dans le domaine de la transplantation pulmonaire, la Bronchiolite Obliterante (BO) reste la complication principale pour la survie a long terme des patients ayant recu un greffon pulmonaire. Consideree comme une consequence du rejet chronique, son mecanisme n’a toujours pas ete completement elucide, notamment en ce qui concerne le role de l’activation cellulaire T in situ. L’implication relative des cellules TH1,TH2 et Treg est toujours inconnue. Methodes L’activation cellulaire T globale a ete evaluee par le phenotypage du marqueur CD69. Les Treg ont ete quantifies par l’expression du marqueur CD25 (fortement exprime). Les cytokines produites (IL-13 et IFN-γ) ont ete quantifiees par cytometrie en flux, apres stimulation par PMA/Ionomycine des Lymphocytes T de l’Expectoration Induite (El) et du Lavage Broncho-Alveolaire (LBA) de patients transplantes pulmonaires (TP). 23 El et LBA de 5 TP avec syndrome de bronchiolite obliterante (SBO) et 18 TP stables (Non SBO) ont ete inclus dans cette etude. Resultats Dans l’expectoration induite, un des marqueurs d’activation des lymphocytes T, le CD69, est plus fortement exprime chez les patients Non SBO que chez les patients SBO. Cependant les Patients SBO produisent plus de cytokines que les Non SBO: IFN-γ (p = 0,0017) et IL-13 (p = 0,0016). Dans le Lavage Broncho-Alveolaire, les cellules T CD25 + sont proportionnellement plus presentes chez les SBO que les Non SBO (p = 0,07). Dans ce compartiment, la quantite de cytokines produite par les Lymphocytes T ne differe pas selon les groupes. Conclusions II existe une compartimentalisation de l’activation cellulaire T que l’on retrouve chez le patient SBO. Cette inflammation se caracterise par un profil TH0 dans l’EI et un profil plutot regulateur dans le LBA.