L Hesse1,2, U Brouwer1,2, A H Petersen3, R Gras1, L Bosman1, J Brimnes4, J N G Oude Elberink2,5, A J M van Oosterhout1,6, M C Nawijn1,2. 1. Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Medical Biology section, Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 4. Department of Experimental Immunology, ALK-Abelló A/S, Hørsholm, Denmark. 5. Division of Allergy, Department of internal medicine, University Medical Centre Groningen, Groningen, The Netherlands. 6. GSK Medicines Research Centre, Stevenage, UK.
Abstract
BACKGROUND: Both subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long-term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking. OBJECTIVE: We aimed to establish an experimental model for grass pollen (GP) SCIT and SLIT that would allow a head-to-head comparison of the two treatments. METHODS: BALB/c mice were sensitized with GP extract, followed by SCIT and SLIT treatments with various GP dosages. Subsequently, we challenged mice with GP and measured airway responsiveness (AHR), GP-specific immunoglobulins, ear swelling tests (EST), eosinophilic inflammation in bronchoalveolar lavage fluid (BALF), and T cell cytokine release after restimulation of lung cells (IL-5, IL-10, and IL-13). RESULTS: We find that SLIT treatment was able to suppress allergen-induced AHR, while allergic inflammation was not effectively suppressed even at the highest GP dose in this model. In contrast, SCIT treatment induced higher levels of GP-specific IgG1, while SLIT was superior in inducing a GP-specific IgG2a response, which was associated with increased Th1 activity in lung tissue after SLIT, but not SCIT treatment. Interestingly, SCIT was able to suppress Th2-type cytokine production in lung cell suspensions, while SLIT failed to do so. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, GP-SCIT suppresses Th2 inflammation and induced neutralizing antibodies, while GP-SLIT suppresses the clinically relevant lung function parameters in an asthma mouse model, indicating that the two application routes depend on partially divergent mechanisms of tolerance induction. Interestingly, these data mirror observations in clinical studies, underscoring the translational value of these mouse models.
BACKGROUND: Both subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long-term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking. OBJECTIVE: We aimed to establish an experimental model for grass pollen (GP) SCIT and SLIT that would allow a head-to-head comparison of the two treatments. METHODS: BALB/c mice were sensitized with GP extract, followed by SCIT and SLIT treatments with various GP dosages. Subsequently, we challenged mice with GP and measured airway responsiveness (AHR), GP-specific immunoglobulins, ear swelling tests (EST), eosinophilic inflammation in bronchoalveolar lavage fluid (BALF), and T cell cytokine release after restimulation of lung cells (IL-5, IL-10, and IL-13). RESULTS: We find that SLIT treatment was able to suppress allergen-induced AHR, while allergic inflammation was not effectively suppressed even at the highest GP dose in this model. In contrast, SCIT treatment induced higher levels of GP-specific IgG1, while SLIT was superior in inducing a GP-specific IgG2a response, which was associated with increased Th1 activity in lung tissue after SLIT, but not SCIT treatment. Interestingly, SCIT was able to suppress Th2-type cytokine production in lung cell suspensions, while SLIT failed to do so. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, GP-SCIT suppresses Th2inflammation and induced neutralizing antibodies, while GP-SLIT suppresses the clinically relevant lung function parameters in an asthma mouse model, indicating that the two application routes depend on partially divergent mechanisms of tolerance induction. Interestingly, these data mirror observations in clinical studies, underscoring the translational value of these mouse models.
Authors: Laura Hesse; Roy Feenstra; Martino Ambrosini; Wim A de Jager; Arjen Petersen; Henk Vietor; Wendy W J Unger; Yvette van Kooyk; Martijn C Nawijn Journal: Allergy Date: 2019-07-08 Impact factor: 13.146
Authors: Laura Hesse; N van Ieperen; Arjen H Petersen; J N G Oude Elberink; Antoon J M van Oosterhout; Martijn C Nawijn Journal: Sci Rep Date: 2020-11-30 Impact factor: 4.379