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Sadeghi M, Dehnavi S, Khodadadi A, Ghadiri AA, Ganji A, Sharifat M, Asadirad A. Immunomodulatory features of MSC-derived exosomes decorated with DC-specific aptamer for improving sublingual immunotherapy in allergic mouse model. Stem Cell Res Ther 2024; 15:481. [PMID: 39696650 DOI: 10.1186/s13287-024-04099-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024] Open
Abstract
INTRODUCTION Sublingual immunotherapy (SLIT) is an effective and injection-free route for allergen-specific immunotherapy (AIT). Mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo) has been identified as a novel delivery platform with immunomodulatory capacities. In addition, targeting agents such as aptamers (Apt) have been extensively used for specific delivery approaches such as direct delivery of allergen formulations to dendritic cells (DC) to improve the efficacy of specific immunotherapy. In this study, we assessed the effects of MSC-derived Exos containing ovalbumin (Ova) which decorated with DC-specific aptamer in allergic rhinitis mice model. MATERIALS AND METHODS Exos were harvested from adipose tissue-derived MSCs, and Exo-Apt-Ova complex was formulated. Then, Ova-induced allergic asthma model was simulated and sensitized BALB/c mice were treated sublingually with Exo-Apt-Ova complex (5 µg Ova) twice weekly for 8 weeks. Ova-specific IgE levels in serum and concentrations of interferon-gamma (IFN-γ), interleukin (IL)-4, and transforming growth factor-beta (TGF-β) in the supernatant of cultured splenocytes were evaluated using enzyme-linked immunosorbent assay (ELISA). In addition, lung histologic analysis and nasopharyngeal lavage fluid (NALF) cell count were performed. RESULTS Administration of Ova-incorporated Apt-modified Exos dramatically increased IFN-γ and TGF-β levels, and decreased IL-4 and IgE levels. In addition, inflammatory responses in the lung tissue and the number of eosinophils in NALF decreased. CONCLUSION SLIT using Exo-Ova (5 µg) decorated with DC-specific aptamer induced immunomodulatory responses and remarkably attenuated allergic airway inflammation in mice.
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Affiliation(s)
- Mahvash Sadeghi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Khodadadi
- Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ata A Ghadiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Ganji
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Moosa Sharifat
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Asadirad
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Dehnavi S, Khodadadi A, Asadirad A, Ghadiri AA. Immune response modulation by allergen loaded into mesenchymal stem cell-derived exosomes as an effective carrier through sublingual immunotherapy. Immunobiology 2023; 228:152361. [PMID: 36870143 DOI: 10.1016/j.imbio.2023.152361] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/27/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023]
Abstract
BACKGROUND Allergen-specific sublingual immunotherapy (SLIT) was considered an interesting needle-free alternative for subcutaneous immunotherapy (SCIT). Mesenchymal stem cell (MSC)-derived exosomes were introduced as potent nanoscale delivery systems with immunomodulatory potentials. The current study investigated the therapeutic efficacy of SLIT using ovalbumin (OVA)-enriched MSC-derived exosomes formulation in a murine model of allergic asthma. MATERIAL AND METHODS MSCs were harvested from mice adipose tissues. Then, exosomes were isolated, and OVA-loaded exosomes were prepared. Following sensitization, Balb/c mice received therapeutic formulation (10 μg/dose OVA-containing MSC-derived exosomes) twice a week for two months. Serum OVA-specific IgE levels as well as IFN-γ, IL-4, and TGF-β secretions by cultured splenocytes were measured by ELISA. Also, lung tissue underwent histopathologic analysis, and the numbers of inflammatory cells and eosinophils in nasopharyngeal lavage fluid (NALF) were examined. RESULTS SLIT using OVA-enriched exosomes significantly reduced IgE levels and IL-4 production, while the secretion of IFN-γ and TGF-β were significantly elevated. Also, a decrease was observed in the numbers of total cells and eosinophils in the NALF, and lower levels of perivascular and peribronchiolar inflammation and cellular infiltrations were observed in the lung tissue. CONCLUSION SLIT using OVA-loaded exosomes improved immunomodulatory responses and efficiently alleviated allergic inflammation.
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Affiliation(s)
- Sajad Dehnavi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Khodadadi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ata A Ghadiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Magnan A, Nicolas JF, Caimmi D, Vocanson M, Haddad T, Colas L, Scurati S, Mascarell L, Shamji MH. Deciphering Differential Behavior of Immune Responses as the Foundation for Precision Dosing in Allergen Immunotherapy. J Pers Med 2023; 13:jpm13020324. [PMID: 36836557 PMCID: PMC9964800 DOI: 10.3390/jpm13020324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/31/2023] [Accepted: 02/07/2023] [Indexed: 02/16/2023] Open
Abstract
Like in many fields of medicine, the concept of precision dosing has re-emerged in routine practice in allergology. Only one retrospective study on French physicians' practice has addressed this topic so far and generated preliminary data supporting dose adaptation, mainly based on experience, patient profile understanding and response to treatment. Both intrinsic and extrinsic factors shape the individual immune system response to allergen immunotherapy (AIT). Herein, we focus on key immune cells (i.e., dendritic cells, innate lymphoid cells, B and T cells, basophils and mast cells) involved in allergic disease and its resolution to further understand the effect of AIT on the phenotype, frequency or polarization of these cells. We strive to discriminate differences in immune responses between responders and non-responders to AIT, and discuss the eligibility of a non/low-responder subset for dose adaptation. A differential behavior in immune cells is clearly observed in responders, highlighting the importance of conducting clinical trials with large cohorts of well-characterized subjects to decipher the immune mechanism of AIT. We conclude that there is a need for designing new clinical and mechanistic studies to support the scientific rationale of dose adaptation in the interest of patients who do not properly respond to AIT.
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Affiliation(s)
- Antoine Magnan
- INRAe UMR 0892, Hôpital Foch, Université de Versailles Saint Quentin, Paris-Saclay, 92150 Suresnes, France
| | - Jean-François Nicolas
- CIRI-International Center for Infectiology Research, INSERM U1111, Lyon1 University, Ecole Normale Supérieure de Lyon, CNRS, UMR 5308, 69007 Lyon, France
| | - Davide Caimmi
- Allergy Unit, Department Respiratory Medicine and Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, 34090 Montpellier, France
| | - Marc Vocanson
- CIRI-International Center for Infectiology Research, INSERM U1111, Lyon1 University, Ecole Normale Supérieure de Lyon, CNRS, UMR 5308, 69007 Lyon, France
| | - Thierry Haddad
- Dermatology, Allergology and Vascular Medicine, Tenon Hospital, 75020 Paris, France
| | - Luc Colas
- Plateforme Transversale d’Allergologie, Clinique Dermatologique, CHU de Nantes, 44093 Nantes, France
- UMR 1064, Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, 44093 Nantes, France
| | - Silvia Scurati
- Stallergenes Greer, 92160 Antony, France
- Correspondence: ; Tel.: +33-(0)-6-12-88-40-93
| | | | - Mohamed H. Shamji
- National Heart & Lung Institute, Imperial College London, London SW7 2AZ, UK
- NIHR Imperial Biomedical Research Centre, London W2 1NY, UK
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Warmenhoven H, Leboux R, Bethanis A, van Strien J, Logiantara A, van Schijndel H, Aglas L, van Rijt L, Slütter B, Kros A, Jiskoot W, van Ree R. Cationic liposomes bearing Bet v 1 by coiled coil-formation are hypo-allergenic and induce strong immunogenicity in mice. FRONTIERS IN ALLERGY 2023; 3:1092262. [PMID: 36704756 PMCID: PMC9872006 DOI: 10.3389/falgy.2022.1092262] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
Although aluminum hydroxide (alum) is widely accepted and used as safe vaccine adjuvant, there is some concern about possible toxicity upon long-lasting repeated exposure during subcutaneous allergen immunotherapy (SCIT). Our objective was to evaluate allergen-bearing liposomes as possible alternative for alum-adsorption in SCIT. A self-assembling, coiled-coil forming peptide pair was used to anchor the major birch pollen allergen Bet v 1 to the surface of cationic liposomes. The resulting nanoparticulate liposomes were characterized with respect to their physicochemical, allergenic and immunological properties. Allergenicity was studied by ImmunoCAP inhibition and rat basophil leukemia (RBL) cell assays. Immunogenicity (immunoglobulin responses) and immune skewing (cytokine responses) were evaluated upon immunization of naïve mice, and compared to alum-adsorbed Bet v 1. Bet v 1-bearing cationic liposomes with a diameter of ∼200 nm showed a positive zeta potential. The coiled-coil conjugation of Bet v 1 to the surface of liposomes resulted in about a 15-fold lower allergenicity than soluble Bet v 1 as judged by RBL assays. Moreover, the nanoparticles induced Bet v 1-specific IgG1/IgG2a responses in mice that were several orders of magnitude higher than those induced by alum-adsorbed Bet v 1. This strong humoral response was accompanied by a relatively strong IL-10 induction upon PBMC stimulation with Bet v 1. In conclusion, their hypo-allergenic properties, combined with their capacity to induce a strong humoral immune response and a relatively strong IL-10 production, makes these allergen-covered cationic liposomes a promising alternative for aluminum salt-adsorption of allergen currently used in SCIT.
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Affiliation(s)
- Hans Warmenhoven
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
- HAL Allergy BV, J.H. Oortweg, Leiden, Netherlands
| | - Romain Leboux
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | | | - Jolinde van Strien
- Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Adrian Logiantara
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
| | | | - Lorenz Aglas
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Leonie van Rijt
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
| | - Bram Slütter
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Alexander Kros
- Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Wim Jiskoot
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Ronald van Ree
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
- Department of Otorhinolaryngology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
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Chenuet P, Marquant Q, Fauconnier L, Youness A, Mellier M, Marchiol T, Rouxel N, Messaoud-Nacer Y, Maillet I, Ledru A, Quesniaux VFJ, Ryffel B, Horsnell W, Végran F, Apetoh L, Togbe D. NLRP6 negatively regulates type 2 immune responses in mice. Allergy 2022; 77:3320-3336. [PMID: 35615773 DOI: 10.1111/all.15388] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 04/05/2022] [Accepted: 05/02/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive. METHODS Wild-type (WT) and Nlrp6-/- mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated. RESULTS We demonstrate in Nlrp6-/- mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6-/- mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6-/- mice. CONCLUSIONS In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses.
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Affiliation(s)
| | - Quentin Marquant
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | | | - Ali Youness
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | | | | | | | - Yasmine Messaoud-Nacer
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | - Isabelle Maillet
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | | | - Valérie F J Quesniaux
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | - Bernhard Ryffel
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
| | - William Horsnell
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France.,Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town 7925, South Africa & South African Medical Research Council, Cape Town, South Africa.,Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | | | | | - Dieudonnée Togbe
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans-Cedex 2, France
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Pei Y, Xiao Z, Wei S, Peng M, Luo C, Wang D. Studies on HBcAg-rBlo t 5-21 Fusion Protein Vaccine That Alleviates Blomia tropicalis Airway Inflammation. J Inflamm Res 2022; 15:6343-6355. [DOI: 10.2147/jir.s380526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 11/06/2022] [Indexed: 11/19/2022] Open
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Gazi U, Bahceciler NN. Immune mechanisms induced by sublingual immunotherapy in allergic respiratory diseases. Clin Exp Immunol 2022; 209:262-269. [PMID: 35975953 PMCID: PMC9521660 DOI: 10.1093/cei/uxac075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/22/2022] [Accepted: 08/15/2022] [Indexed: 01/25/2023] Open
Abstract
Allergic respiratory diseases (ARDs) are still a major burden on global public health. Sublingual immunotherapy (SLIT) is a mode of allergen immunotherapy (AIT) which involves administration of the allergen under the tongue, and benefits from tolerogenic properties of the oral mucosa. Studies revealed reduced levels of eosinophilia and eosinophil-dominated inflammation in airways of both animals and humans after SLIT. SLIT was also suggested to lower basophil responsiveness and innate lymphoid cell-2 function in blood samples collected from patients with ARD. Moreover, apart from shifting pathogenic type 2 (TH2) to a type 1 (TH1) and protective regulatory (Treg) polarization of helper T-cell immune response, antibody isotype switch from IgE to IgG1, IgG2, IgG4 and IgA was also reported in patients with ARD receiving SLIT. Today, the literature on SLIT-mediated activities is still scarce and more studies are required to further enlighten the mechanisms utilized by SLIT for the induction of tolerance. The aim of this review is to summarize the current knowledge about the immune-regulatory mechanisms induced by SLIT against ARDs.
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Affiliation(s)
- Umut Gazi
- Department of Medical Microbiology and Clinical Microbiology, Faculty of Medicine, Near East University, Nicosia, Cyprus
| | - Nerin Nadir Bahceciler
- Department of Pediatrics, Division of Allergy and Immunology, Faculty of Medicine, Near East University, Nicosia, Cyprus
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Yang J, Bae J, Choi CY, Choi SP, Yun HS, Chun T. Oral administration of Lactiplantibacillus plantarum NR16 isolated from Kimchi ameliorates murine allergic rhinitis. Lett Appl Microbiol 2022; 75:152-160. [PMID: 35388497 DOI: 10.1111/lam.13716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 11/30/2022]
Abstract
Allergic rhinitis (AR) is a type I hypersensitivity mediated by dominant T helper 2 (Th2) response over the Th1 response after re-exposure to a specific allergen. Currently, socio-economic cost evoked by AR is quickly increasing since the prevalence of AR is gradually increasing in all ages worldwide. Several probiotic Lactobacillus strains have been described with potential immunomodulatory effects against type I hypersensitivity such as AR. Thus, the aim of the present work was to characterize basic probiotic property and immunomodulatory role of newly isolated Lactobacillus strains from Kimchi, a traditional fermented Korean food, in allergic rhinitis. Among the identified strains, Lactiplantibacillus plantarum NR16 revealed to be a powerful Th1 inducer since immune cells co-cultured with NR16 produced the highest quantity of interferon-γ (IFN-γ) and interleukin-12 (IL-12) but secreted a low amount of IL-4 in vitro. Therefore, NR16 was selected for the following assays conducted with mice with birch pollen-induced allergic rhinitis. Oral administration of NR16 reduced airway hyperresponsiveness and leukocyte infiltration in lesions of mice. In conclusion, oral administration of NR16 may mitigate symptoms of allergic rhinitis by inducing Th1 immune response, which might rebalance Th2/Th1 ratio by decreasing Th2 cytokine production in specific lesions of mucosa.
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Affiliation(s)
- J Yang
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - J Bae
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - C-Y Choi
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - S-P Choi
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - H S Yun
- Health R&D Center, CJ CheilJedang Corporation, Suwon-si, 16495, Republic of Korea
| | - T Chun
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
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Sadeghi M, Keshavarz Shahbaz S, Dehnavi S, Koushki K, Sankian M. Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy. Int Immunopharmacol 2021; 101:108350. [PMID: 34782275 DOI: 10.1016/j.intimp.2021.108350] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 10/19/2022]
Abstract
Allergen-specific sublingual immunotherapy (SLIT), a safe and efficient route for treating type I hypersensitivity disorders, requires high doses of allergens. SLIT is generally performed without adjuvants and delivery systems. Therefore, allergen formulation with appropriate presentation platforms results in improved allergen availability, targeting the immune cells, inducing regulatory immune responses, and enhancing immunotherapy's efficacy while decreasing the dose of the allergen. In this review, we discuss the adjuvants and delivery systems that have been applied as allergen-presentation platforms for SLIT. These adjuvants include TLRs ligands, 1α, 25-dihydroxy vitamin D3, galectin-9, probiotic and bacterial components that provoke allergen-specific helper type-1 T lymphocytes (TH1), and regulatory T cells (Tregs). Another approach is encapsulation or adsorption of the allergens into a particulate vector system to facilitate allergen capture by tolerogenic dendritic cells. Also, we proposed strategies to increasing the efficacy of SLIT via new immunopotentiators and carrier systems in the future.
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Affiliation(s)
- Mahvash Sadeghi
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sajad Dehnavi
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Khadijeh Koushki
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mojtaba Sankian
- Immunobiochemistry Lab, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Protić-Rosić I, Nešić A, Lukić I, Miljković R, Popović DM, Atanasković-Marković M, Stojanović M, Gavrović-Jankulović M. Recombinant Bet v 1-BanLec chimera modulates functional characteristics of peritoneal murine macrophages by promoting IL-10 secretion. Mol Immunol 2021; 138:58-67. [PMID: 34364073 DOI: 10.1016/j.molimm.2021.06.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 05/27/2021] [Accepted: 06/22/2021] [Indexed: 11/28/2022]
Abstract
Allergen-specific immunotherapy (AIT) is a desensitizing treatment for allergic diseases that corrects the underlined pathological immune response to innocuous protein antigens, called allergens. Recombinant allergens employed in the AIT allowed the production of well-defined formulations that possessed consistent quality but were often less efficient than natural allergen extracts. Combining recombinant allergens with an adjuvant or immunomodulatory agent could improve AIT efficacy. This study aimed to perform structural and functional characterization of newly designed recombinant chimera composed of the Bet v 1, the major birch pollen allergen, and Banana Lectin (BanLec), TLR2, and CD14 binding protein, for the application in AIT. rBet v 1-BanLec chimera was designed in silico and expressed as a soluble fraction in Escherichia coli. Purified rBet v 1-BanLec (33.4 kDa) retained BanLec-associated biological activity of carbohydrate-binding and preserved IgE reactive epitopes of Bet v 1. The chimera revealed secondary structures with predominant β sheets. The immunomodulatory capacity of rBet v 1-BanLec tested on macrophages showed changes in myeloperoxidase activity, reduced NO production, and significant alterations in the production of cytokines when compared to both rBanLec and rBet v 1. Comparing to rBet v 1, rBet v 1-BanLec was demonstrated to be more efficient promoter of IL-10 production as well as weaker inducer of NO production and secretion of pro-inflammatory cytokines TNFα, and IL-6. The ability of rBet v 1-BanLec to promote IL-10 in together with the preserved 3D structure of Bet v 1 part implies that the construct might exert a beneficial effect in the allergen-specific immunotherapy.
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Affiliation(s)
- Isidora Protić-Rosić
- Department of Biochemistry, Faculty of Chemistry University of Belgrade, Belgrade, Serbia
| | - Andrijana Nešić
- Department of Biochemistry, Faculty of Chemistry University of Belgrade, Belgrade, Serbia
| | - Ivana Lukić
- Department of Research and Development, Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia
| | - Radmila Miljković
- Department of Research and Development, Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia
| | - Dragan M Popović
- University of Belgrade - Institute of Chemistry, Technology and Metallurgy - National Institute of the Republic of Serbia, Belgrade, Serbia
| | - Marina Atanasković-Marković
- Department of Allergology and Pulmonology, University Children's Hospital, Medical Faculty University of Belgrade, Belgrade, Serbia
| | - Marijana Stojanović
- Department of Research and Development, Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia
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Airouche S, Beltrami V, Fleury S, Batard T, Bordas-Le Floch V, Stegmann T, Amacker M, Kettner A, Mascarell L. Bet v 1 contiguous overlapping peptides anchored to virosomes with TLR4 agonist enhance immunotherapy efficacy in mice. Clin Exp Allergy 2021; 51:339-349. [PMID: 33368719 DOI: 10.1111/cea.13814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/30/2020] [Accepted: 12/15/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Whereas sublingual allergen immunotherapy (AIT) is routinely performed without any adjuvant or delivery system, there is a strong scientific rationale to better target the allergen(s) to oral dendritic cells known to support regulatory immune responses by using appropriate presentation platforms. OBJECTIVE To identify a safe presentation platform able to enhance allergen-specific tolerance induction. METHODS Virosomes with membrane-integrated contiguous overlapping peptides (COPs) of Bet v 1 and TLR4 or TLR2/TLR7 agonists were assessed for induction of Bet v 1-specific IgG1, IgG2a and IgE antibodies, hypersensitivity reactions and body temperature drop following subcutaneous injection in naive CD-1 mice. The most promising candidate, Bet v 1 COPs anchored to virosomes with membrane-incorporated TLR4 agonist (Vir.A-Bet v 1 COPs), was further evaluated by the sublingual route in a therapeutic setting in BALB/c mice with birch pollen-induced allergic asthma. Airway hyperresponsiveness, pro-inflammatory cells in bronchoalveolar lavages and polarization of Th cells in the lungs and spleen were then assessed. RESULTS Both types of adjuvanted virosomes coupled to Bet v 1 COPs triggered a boosted Th1 immunity. Given a more favourable safety profile, Vir.A-Bet v 1 COPs were further evaluated and shown to able to fully reverse asthma symptoms and lung inflammation in a sublingual therapeutic model of birch pollen allergy. CONCLUSIONS AND CLINICAL RELEVANCE We report herein for the first time on the capacity of a novel and safe presentation platform, that is virosomes with membrane-integrated TLR4 agonist, to improve dramatically sublingual AIT efficacy in a murine model due to its intrinsic dual properties of targeting and stimulating to further promote anti-allergic immune responses. As such, our study paves the ground for further clinical development of this allergen presentation platform for patients suffering from respiratory allergies.
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Affiliation(s)
| | | | | | | | | | | | - Mario Amacker
- Mymetics SA, Epalinges, Switzerland.,Department of Pulmonary Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
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12
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Pali-Schöll I, DeBoer DJ, Alessandri C, Seida AA, Mueller RS, Jensen-Jarolim E. Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon. Front Immunol 2020; 11:1697. [PMID: 32849594 PMCID: PMC7417425 DOI: 10.3389/fimmu.2020.01697] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 06/25/2020] [Indexed: 12/20/2022] Open
Abstract
Allergen immunotherapy is currently the only causal treatment for allergic diseases in human beings and animals. It aims to re-direct the immune system into a tolerogenic or desensitized state. Requirements include clinical efficacy, safety, and schedules optimizing patient or owner compliance. To achieve these goals, specific allergens can be formulated with adjuvants that prolong tissue deposition and support uptake by antigen presenting cells, and/or provide a beneficial immunomodulatory action. Here, we depict adjuvant formulations being investigated for human and veterinary allergen immunotherapy.
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Affiliation(s)
- Isabella Pali-Schöll
- University of Veterinary Medicine, Vienna, Austria.,Institute of Pathophysiology and Allergy Research, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Douglas J DeBoer
- Dermatology/Allergy Section, Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, United States
| | | | - Ahmed Adel Seida
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Ralf S Mueller
- Centre for Clinical Veterinary Medicine, University of Munich, Munich, Germany
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy Research, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria
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13
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Dona DW, Suphioglu C. Egg Allergy: Diagnosis and Immunotherapy. Int J Mol Sci 2020; 21:E5010. [PMID: 32708567 PMCID: PMC7404024 DOI: 10.3390/ijms21145010] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/03/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Hypersensitivity or an allergy to chicken egg proteins is a predominant symptomatic condition affecting 1 in 20 children in Australia; however, an effective form of therapy has not yet been found. This occurs as the immune system of the allergic individual overreacts when in contact with egg allergens (egg proteins), triggering a complex immune response. The subsequent instantaneous inflammatory immune response is characterized by the excessive production of immunoglobulin E (IgE) antibody against the allergen, T-cell mediators and inflammation. Current allergen-specific approaches to egg allergy diagnosis and treatment lack consistency and therefore pose safety concerns among anaphylactic patients. Immunotherapy has thus far been found to be the most efficient way to treat and relieve symptoms, this includes oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). A major limitation in immunotherapy, however, is the difficulty in preparing effective and safe extracts from natural allergen sources. Advances in molecular techniques allow for the production of safe and standardized recombinant and hypoallergenic egg variants by targeting the IgE-binding epitopes responsible for clinical allergic symptoms. Site-directed mutagenesis can be performed to create such safe hypoallergens for their potential use in future methods of immunotherapy, providing a feasible standardized therapeutic approach to target egg allergies safely.
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Affiliation(s)
| | - Cenk Suphioglu
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong 3216 VIC, Australia;
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14
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Floris I, Chenuet P, Togbe D, Volteau C, Lejeune B. Potential Role of the Micro-Immunotherapy Medicine 2LALERG in the Treatment of Pollen-Induced Allergic Inflammation. Dose Response 2020; 18:1559325820914092. [PMID: 32269504 PMCID: PMC7093691 DOI: 10.1177/1559325820914092] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 02/19/2020] [Accepted: 02/25/2020] [Indexed: 12/22/2022] Open
Abstract
In this study, we evaluated the efficacy of a micro-immunotherapy medicine (MIM),
2LALERG, in a preclinical model of allergic respiratory disease sensitized with
birch pollen extract (BPE). BALB/c mice were immunized with BPE, or saline
solution, and were then challenged. Micro-immunotherapy medicine pillules were
diluted in water, and 3 doses (0.75; 1.5; 3 mg/mouse) were tested and compared
to vehicle control (3 mg/mouse). Treatments and vehicle were orally administered
by gavage for 10 days. Micro-immunotherapy medicine (0.75 mg/mouse) reduced the
number of total cells as well as the levels of interleukin (IL)-13 in
bronchoalveolar lavage fluid (BALF) compared to vehicle control. Eosinophils in
BALF tended to be lower compared to vehicle group, and the difference is close
to significance. Histological analysis in the lungs confirms a moderate effect
of MIM (0.75 mg/mice) on inflammatory infiltration and mucus production. Serum
levels of IL-5 in MIM (0.75 mg/mouse)-treated mice were lower compared to
vehicle; IL-4 levels tended to be lower too. Total immunoglobulin E (IgE)
decreased in serum of MIM (1.5 and 0.75 mg/mouse) groups compared to vehicle
control. Micro-immunotherapy medicine exerted the highest effect at the lowest
dose tested. Micro-immunotherapy medicine resolved the local and systemic
inflammation, even if partially, in a model of pollen-induced, IgE-mediated
inflammation.
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Affiliation(s)
- Ilaria Floris
- Preclinical & Clinical Development and Regulatory Affairs, Labo'Life France, Nantes, France
| | | | | | - Christelle Volteau
- Preclinical & Clinical Development and Regulatory Affairs, Labo'Life France, Nantes, France
| | - Beatrice Lejeune
- Preclinical & Clinical Development and Regulatory Affairs, Labo'Life France, Nantes, France
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15
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Hajavi J, Hashemi M, Sankian M. Evaluation of size and dose effects of rChe a 3 allergen loaded PLGA nanoparticles on modulation of Th2 immune responses by sublingual immunotherapy in mouse model of rhinitis allergic. Int J Pharm 2019; 563:282-292. [DOI: 10.1016/j.ijpharm.2019.03.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 03/11/2019] [Accepted: 03/18/2019] [Indexed: 01/08/2023]
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16
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Hesse L, Brouwer U, Petersen AH, Gras R, Bosman L, Brimnes J, Oude Elberink JNG, van Oosterhout AJM, Nawijn MC. Subcutaneous immunotherapy suppresses Th2 inflammation and induces neutralizing antibodies, but sublingual immunotherapy suppresses airway hyperresponsiveness in grass pollen mouse models for allergic asthma. Clin Exp Allergy 2018; 48:1035-1049. [PMID: 29752757 DOI: 10.1111/cea.13169] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 03/30/2018] [Accepted: 05/01/2018] [Indexed: 01/05/2023]
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.
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Affiliation(s)
- L Hesse
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - U Brouwer
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - A H Petersen
- Medical Biology section, Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - R Gras
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - L Bosman
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Brimnes
- Department of Experimental Immunology, ALK-Abelló A/S, Hørsholm, Denmark
| | - J N G Oude Elberink
- Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Division of Allergy, Department of internal medicine, University Medical Centre Groningen, Groningen, The Netherlands
| | - A J M van Oosterhout
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,GSK Medicines Research Centre, Stevenage, UK
| | - M C Nawijn
- Department of Pathology & Medical Biology, Experimental Pulmonary and Inflammatory Research (EXPIRE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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17
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Choi SP, Oh HN, Choi CY, Ahn H, Yun H, Chung Y, Kim B, Lee S, Chun T. Oral administration of Lactobacillus plantarum
CJLP133 and CJLP243 alleviates birch pollen-induced allergic rhinitis in mice. J Appl Microbiol 2018; 124:821-828. [DOI: 10.1111/jam.13635] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 09/01/2017] [Accepted: 11/02/2017] [Indexed: 12/23/2022]
Affiliation(s)
- S.-P. Choi
- Department of Biotechnology; College of Life Sciences and Biotechnology; Korea University; Seoul Korea
| | - H.-N. Oh
- Department of Biotechnology; College of Life Sciences and Biotechnology; Korea University; Seoul Korea
| | - C.-Y. Choi
- Department of Biotechnology; College of Life Sciences and Biotechnology; Korea University; Seoul Korea
| | - H. Ahn
- CJ CheilJedang Corporation; Suwon-si Korea
| | - H.S. Yun
- CJ CheilJedang Corporation; Suwon-si Korea
| | - Y.M. Chung
- CJ CheilJedang Corporation; Suwon-si Korea
| | - B. Kim
- CJ CheilJedang Corporation; Suwon-si Korea
| | - S.J. Lee
- Department of Biomedical Laboratory Science; College of Health Science; Cheongju University; Cheongju-si Korea
| | - T. Chun
- Department of Biotechnology; College of Life Sciences and Biotechnology; Korea University; Seoul Korea
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18
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Cook QS, Burks AW. Peptide and Recombinant Allergen Vaccines for Food Allergy. Clin Rev Allergy Immunol 2018; 55:162-171. [DOI: 10.1007/s12016-018-8673-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Moingeon P, Lombardi V, Baron-Bodo V, Mascarell L. Enhancing Allergen-Presentation Platforms for Sublingual Immunotherapy. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2017; 5:23-31. [PMID: 28065340 DOI: 10.1016/j.jaip.2016.07.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/22/2016] [Accepted: 07/25/2016] [Indexed: 01/24/2023]
Abstract
Sublingual immunotherapy (SLIT) relies on high doses of allergens to treat patients with type I allergies. Although SLIT is commonly performed without any adjuvant or delivery system, allergen(s) could be further formulated with allergen-presentation platforms to better target oral dendritic cells eliciting regulatory immune responses. Improving the availability of allergens to the immune system should enhance SLIT efficacy, while allowing to decrease allergen dosing. Herein, we present an overview of adjuvants and vector systems that have been, or could be, considered as candidate allergen-presentation platforms for the sublingual route. Such platforms encompass adjuvants capable of stimulating allergen-specific TH1 and/or regulatory CD4+ T-cell responses, including 1,25-dihydroxy vitamin D3, glucocorticoids, Toll-like receptor ligands as well as selected bacterial probiotic strains. A limiting factor for SLIT efficacy is the number of dendritic cells capturing the allergens in the upper layers of oral tissues. Thus, adsorption or encapsulation of the allergen(s) within mucoadhesive particulate vector (or delivery) systems also has the potential to significantly enhance SLIT efficacy due to a facilitated allergen uptake by tolerogenic oral dendritic cells.
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Affiliation(s)
- P Moingeon
- Research and Development, Stallergenes Greer, Antony, France.
| | - V Lombardi
- Research and Development, Stallergenes Greer, Antony, France
| | - V Baron-Bodo
- Research and Development, Stallergenes Greer, Antony, France
| | - L Mascarell
- Research and Development, Stallergenes Greer, Antony, France
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20
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Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products. PLoS One 2017; 12:e0183398. [PMID: 28886055 PMCID: PMC5590855 DOI: 10.1371/journal.pone.0183398] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 08/03/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species. METHODS Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue. RESULTS Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species. CONCLUSION The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.
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21
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Moingeon P, Mascarell L. Differences and similarities between sublingual immunotherapy of allergy and oral tolerance. Semin Immunol 2017; 30:52-60. [PMID: 28760498 DOI: 10.1016/j.smim.2017.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 07/13/2017] [Indexed: 12/27/2022]
Abstract
Allergen immunotherapy is the only treatment altering the natural course of IgE-mediated allergies. Whereas the subcutaneous route for immunotherapy (SCIT) has been historically considered as a reference, we discuss herein the relative advantages of the sublingual and oral routes as alternatives to SCIT in order to elicit allergen-specific tolerance. The buccal and gut immune systems are similarly organized to favor immune tolerance to antigens/allergens, due to the presence of tolerogenic dendritic cells and macrophages promoting the differentiation of CD4+ regulatory T cells. Sublingual immunotherapy (SLIT) is now established as a valid treatment option, with clinical efficacy demonstrated in allergic rhinoconjunctivitis (to either grass, tree, weed pollens or mite allergens) and encouraging results obtained in the management of mild/moderate allergic asthma. While still exploratory, oral immunotherapy (OIT) has shown promising results in the desensitization of patients with food allergies. We review at both biological and clinical levels the perspectives currently pursued for those two mucosal routes.
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Affiliation(s)
- Philippe Moingeon
- Research Department, Stallergenes Greer, 6 rue Alexis de Tocqueville, 92160 Antony, France.
| | - Laurent Mascarell
- Research Department, Stallergenes Greer, 6 rue Alexis de Tocqueville, 92160 Antony, France
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22
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Shima K, Koya T, Tsukioka K, Sakagami T, Hasegawa T, Fukano C, Ohashi-Doi K, Watanabe S, Suzuki E, Kikuchi T. Effects of sublingual immunotherapy in a murine asthma model sensitized by intranasal administration of house dust mite extracts. Allergol Int 2017; 66:89-96. [PMID: 27397923 DOI: 10.1016/j.alit.2016.05.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 05/07/2016] [Accepted: 05/21/2016] [Indexed: 10/21/2022] Open
Abstract
BACKGROUND Sublingual immunotherapy (SLIT) has received attention as a method for allergen immunotherapy. However, the mechanism of SLIT has not yet been fully investigated. Therefore, we evaluated the effects of SLIT in a murine asthma model, sensitized by intranasal administration of house dust mite (HDM) extracts. METHODS Female BALB/c mice were intranasally exposed to HDM for either 3 or 5 weeks (5 consecutive days per week). Mice were administered either low-dose (0.5 mg/day) or high-dose (5 mg/day) sublingual HDM extracts for 2 weeks, followed by an additional week of intranasal exposure. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, cytokine levels in the BALF and lymph node cell culture supernatants, and allergen-specific antibodies were measured. Lung histology was also investigated. RESULTS In mice sensitized for 5 weeks, high-dose SLIT ameliorated AHR, airway eosinophilia and goblet cell metaplasia. In mice sensitized for 3 weeks, even low dose SLIT ameliorated AHR and airway eosinophilia. Th2 cytokine levels in culture supernatants of submandibular lymph node cells in high-dose SLIT mice decreased, whereas IL-10 levels increased. Total IgA in BALF increased in mice sensitized for 3 or 5 weeks, and high-dose SLIT also increased allergen-specific IgG2a in mice sensitized for 5 weeks. CONCLUSIONS These data suggest that earlier induction of SLIT in HDM-sensitized mice provides superior suppression of AHR and goblet cell metaplasia. The modulation of allergen specific IgG2a and local IgA might play a role in the amelioration of AHR and airway inflammation.
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Hagner S, Rask C, Brimnes J, Andersen PS, Raifer H, Renz H, Garn H. House Dust Mite-Specific Sublingual Immunotherapy Prevents the Development of Allergic Inflammation in a Mouse Model of Experimental Asthma. Int Arch Allergy Immunol 2016; 170:22-34. [PMID: 27287860 DOI: 10.1159/000446155] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 04/11/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Evidence regarding sublingual immunotherapy (SLIT) efficacy and its good safety profile has been demonstrated with pollen and house dust mite (HDM) allergens in the treatment of airway allergies. In addition, the use of grass pollen presents a SLIT disease-modifying treatment for respiratory allergies. OBJECTIVES The aim of this study was to demonstrate the efficacy of HDM-based SLIT in mouse models of allergic airway inflammation and to gain insights into the involved local immunological mechanisms. METHODS Balb/c mice were sensitized/challenged with Dermatophagoides farinae (Der f) extract and underwent Der f-SLIT in prophylactic and therapeutic settings. The SLIT efficacy was assessed using lung function measurements, analysis of local inflammatory responses by bronchoalveolar lavage cell differentiation and lung histology. Humoral and cellular responses were monitored by ELISA, cytokine bead array and flow cytometry analyses. RESULTS In a prophylactic setting, Der f-SLIT with 12 development units per dose reduced the eosinophil-dominated inflammatory response in the lung paralleled by a marked reduction in airway hyperresponsiveness. Local Th2 responses were prevented as demonstrated by significantly lower levels of IL-5 and IL-13. Additionally, SLIT-treated mice revealed a lower proportion of CD4-CD8- x03B3;δ cells and a higher frequency of CD8+CD25+IFNx03B3;+ T cells in the lungs compared to sham-treated mice. In a therapeutic setting, Der f-SLIT also resulted in reduced inflammatory responses in the lung. CONCLUSION The efficacy of Der f-SLIT was demonstrated in prophylactic and therapeutic conditions using experimental mouse models of HDM-induced airway inflammation. A potential role of a so far underestimated lymphocyte subpopulation was also indicated.
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Affiliation(s)
- Stefanie Hagner
- Institute of Laboratory Medicine, Center for Tumor and Immunobiology (ZTI), Medical Faculty, Philipps University of Marburg, Marburg, Germany
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Moingeon P, Floch VBL, Airouche S, Baron-Bodo V, Nony E, Mascarell L. Allergen immunotherapy for birch pollen-allergic patients: recent advances. Immunotherapy 2016; 8:555-67. [DOI: 10.2217/imt-2015-0027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
As of today, allergen immunotherapy is performed with aqueous natural allergen extracts. Recombinant allergen vaccines are not yet commercially available, although they could provide patients with well-defined and highly consistent drug substances. As Bet v 1 is the major allergen involved in birch pollen allergy, with more than 95% of patients sensitized to this allergen, pharmaceutical-grade recombinant Bet v 1-based vaccines were produced and clinically tested. Herein, we compare the clinical results and modes of action of treatments based on either a birch pollen extract or recombinant Bet v 1 expressed as hypoallergenic or natural-like molecules. We also discuss the future of allergen immunotherapy with improved drugs intended for birch pollen-allergic patients suffering from rhinoconjunctivitis.
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Affiliation(s)
- Philippe Moingeon
- Stallergenes Greer, Research Department, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France
| | | | - Sabi Airouche
- Stallergenes Greer, Research Department, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France
| | - Véronique Baron-Bodo
- Stallergenes Greer, Research Department, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France
| | - Emmanuel Nony
- Stallergenes Greer, Research Department, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France
| | - Laurent Mascarell
- Stallergenes Greer, Research Department, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France
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25
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Nony E, Bouley J, Le Mignon M, Lemoine P, Jain K, Horiot S, Mascarell L, Pallardy M, Vincentelli R, Leone P, Roussel A, Batard T, Abiteboul K, Robin B, de Beaumont O, Arvidsson M, Rak S, Moingeon P. Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients. Allergy 2015; 70:795-804. [PMID: 25846209 DOI: 10.1111/all.12622] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND Sublingual immunotherapy (SLIT) applied to type I respiratory allergies is commonly performed with natural allergen extracts. Herein, we developed a sublingual tablet made of pharmaceutical-grade recombinant Bet v 1.0101 (rBet v 1) and investigated its clinical safety and efficacy in birch pollen (BP)-allergic patients. METHODS Following expression in Escherichia coli and purification, rBet v 1 was characterized using chromatography, capillary electrophoresis, circular dichroism, mass spectrometry and crystallography. Safety and efficacy of rBet v 1 formulated as a sublingual tablet were assessed in a multicentre, double-blind, placebo-controlled study conducted in 483 patients with BP-induced rhinoconjunctivitis. RESULTS In-depth characterization confirmed the intact product structure and high purity of GMP-grade rBet v 1. The crystal structure resolved at 1.2 Å documented the natural conformation of the molecule. Native or oxidized forms of rBet v 1 did not induce the production of any proinflammatory cytokine by blood dendritic cells or mononuclear cells. Bet v 1 tablets were well tolerated by patients, consistent with the known safety profile of SLIT. The average adjusted symptom scores were significantly decreased relative to placebo in patients receiving once daily for 5 months rBet v 1 tablets, with a mean difference of 17.0-17.7% relative to the group treated with placebo (P < 0.025), without any influence of the dose in the range (12.5-50 μg) tested. CONCLUSION Recombinant Bet v 1 has been produced as a well-characterized pharmaceutical-grade biological drug. Sublingual administration of rBet v 1 tablets is safe and efficacious in patients with BP allergic rhinoconjunctivitis.
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Affiliation(s)
| | | | | | | | | | | | | | - M. Pallardy
- UFR Pharmacie Paris 11; Châtenay-Malabry France
| | | | - P. Leone
- Structural Immunology; AFMB-UMR7257; Marseille France
| | - A. Roussel
- Structural Immunology; AFMB-UMR7257; Marseille France
| | | | | | | | | | - M. Arvidsson
- Department of Respiratory Medicine and Allergology; Sahlgrenska University Hospital; Goteborg Sweden
| | - S. Rak
- Department of Respiratory Medicine and Allergology; Sahlgrenska University Hospital; Goteborg Sweden
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Abstract
PURPOSE OF REVIEW Allergen-specific immunotherapy is the only curative treatment for allergic diseases. In spite of the great progress in both vaccine development and the methods of allergen immunotherapy (AIT) in recent years, several key problems related to limited efficacy, side-effects, low patient adherence and the relatively high costs due to the long duration (3-5 years) remain to be solved. The current approaches aiming at optimization of AIT are reviewed, including both conceptual studies in experimental models and proof-of-concept - as well as large, multicenter clinical studies. RECENT FINDINGS The most promising approaches to improve efficacy and safety of vaccine-based AIT include bypassing IgE binding and targeting allergen-specific T cells using hypoallergenic recombinant allergen derivatives and immunogenic peptides, the use of new adjuvants and stimulators of the innate immune response, the fusion of allergens to immune modifiers and peptide carrier proteins and new routes of vaccine administration. SUMMARY The cloning of allergen proteins and genetic engineering enabled the production of vaccines that have well defined molecular, immunologic and biologic characteristics as well as modified molecular structure. These new compounds along with new immunization protocols can bring us closer to the ultimate goal of AIT, that is, complete cure of a large number of allergic patients.
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Abstract
Allergen-specific immunotherapy is the only treatment of allergic diseases that aims at modifying the underlying immune mechanism. Current protocols are long and at risk of anaphylactic reactions. The main aim of current research is decreasing the risk of side effects and increasing efficacy, in particular targeting reduction of treatment duration. Since the advent of molecular biology, extracts can be replaced by recombinant hypo-allergens, peptides, or fusion proteins. In addition, different routes of administration are being pursued as well as the addition of new adjuvants that are targeted at skewing the immune system away from a Th2 to a more Th1 or regulatory T cell phenotype. In this review, we summarize the recent advances in this field focusing on the allergen modifications and new adjuvants.
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van Rijt LS, Gouveia L, Logiantara A, Canbaz D, Opstelten DJ, van der Kleij HPM, van Ree R. Birch pollen immunotherapy in mice: inhibition of Th2 inflammation is not sufficient to decrease airway hyper-reactivity. Int Arch Allergy Immunol 2014; 165:128-39. [PMID: 25412572 DOI: 10.1159/000368777] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 09/29/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Suppression of Th2 cytokine production by allergen-specific Th2 cells is considered to be critical for the suppression of allergic symptoms by subcutaneous immunotherapy. The aim of this study was to develop a mouse model for birch pollen (BP) immunotherapy to elucidate the underlying mechanisms that contribute to the improvement of clinical symptoms. METHODS Mice with BP-induced allergic airway inflammation received weekly subcutaneous immunotherapy (SCIT) injections with BP extract (BPE) adsorbed to alum. The effect of an increasing dose of BPE adsorbed to a fixed concentration of alum on the suppression of airway inflammation and airway hyper-responsiveness (AHR) was determined. After 2, 4, 6 or 8 immunotherapy injections, the mice were rechallenged with the same allergen and all hallmarks of allergic asthma were evaluated. RESULTS Suppression of the immunological parameters by immunotherapy was dependent on the BPE dose. Two injections were sufficient to suppress IL-4, IL-5, IL-13, IL-10 and IFN-γ production, eosinophil recruitment and peribronchial inflammatory infiltrates. BP-specific immunoglobulins were upregulated, but this was not sufficient to reduce AHR. Eight injections were needed to suppress AHR. The gradual reduction in AHR was inversely associated with the increase of BP IgG2a. CONCLUSIONS BP SCIT induces an early suppression of Th2-mediated eosinophilic airway inflammation, but AHR is only effectively reduced after continued SCIT conceivably by allowing IgG2a antibody titres to build up.
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Affiliation(s)
- Leonie S van Rijt
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
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Popescu FD. Molecular biomarkers for grass pollen immunotherapy. World J Methodol 2014; 4:26-45. [PMID: 25237628 PMCID: PMC4145574 DOI: 10.5662/wjm.v4.i1.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 01/05/2014] [Accepted: 02/18/2014] [Indexed: 02/06/2023] Open
Abstract
Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines.
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Marth K, Focke-Tejkl M, Lupinek C, Valenta R, Niederberger V. Allergen Peptides, Recombinant Allergens and Hypoallergens for Allergen-Specific Immunotherapy. CURRENT TREATMENT OPTIONS IN ALLERGY 2014; 1:91-106. [PMID: 24860720 PMCID: PMC4025905 DOI: 10.1007/s40521-013-0006-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Allergic diseases are among the most common health issues worldwide. Specific immunotherapy has remained the only disease-modifying treatment, but it is not effective in all patients and may cause side effects. Over the last 25 years, allergen molecules from most prevalent allergen sources have been isolated and produced as recombinant proteins. Not only are these molecules useful in improved allergy diagnosis, but they also have the potential to revolutionize the treatment of allergic disease by means of immunotherapy. Panels of unmodified recombinant allergens have already been shown to effectively replace natural allergen extracts in therapy. Through genetic engineering, several molecules have been designed with modified immunological properties. Hypoallergens have been produced that have reduced IgE binding capacity but retained T cell reactivity and T cell peptides which stimulate allergen-specific T cells, and these have already been investigated in clinical trials. New vaccines have been recently created with both reduced IgE and T cell reactivity but retained ability to induce protective allergen-specific IgG antibodies. The latter approach works by fusing per se non-IgE reactive peptides derived from IgE binding sites of the allergens to a virus protein, which acts as a carrier and provides the T-cell help necessary for immune stimulation and protective antibody production. In this review, we will highlight the different novel approaches for immunotherapy and will report on prior and ongoing clinical studies.
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Affiliation(s)
- Katharina Marth
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Margarete Focke-Tejkl
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Christian Lupinek
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Rudolf Valenta
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Verena Niederberger
- Department of Otorhinolaryngology, Medical University of Vienna, Vienna General Hospital, AKH 8J, 1090 Vienna, Austria
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Corthésy B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol 2013; 4:185. [PMID: 23874333 PMCID: PMC3709412 DOI: 10.3389/fimmu.2013.00185] [Citation(s) in RCA: 428] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 06/24/2013] [Indexed: 01/06/2023] Open
Abstract
Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer’s patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.
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Affiliation(s)
- Blaise Corthésy
- R&D Laboratory, Department of Immunology and Allergy, University State Hospital Lausanne (CHUV) , Lausanne , Switzerland
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