Abstract
Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.
Highlights
Bronchial asthma is a chronic airway inflammatory condition involving mainly eosinophils but with contributions from many other cell types and inflammatory mediators [1,2]
Compared with Dendritic cells (DCs) treated with OVA alone or Recombinant adenovirus (rAdV)-green fluorescent protein (GFP), rAdV-cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) modification significantly suppressed CD80 and CD86 expression without influencing the expression of MHC-II on the surface of DCs
The mixed lymphocyte reaction (MLR) tests showed that OVA and OVA+rAdV-GFP-treated DCs resulted in the stimulation of T cells
Summary
Bronchial asthma is a chronic airway inflammatory condition involving mainly eosinophils but with contributions from many other cell types and inflammatory mediators [1,2]. Allergen-specific immunotherapy (ASIT) is the only treatment that affects the natural progress of allergic diseases [4,5]. The principle of ASIT is to induce and maintain allergen-specific T cell peripheral immune tolerance [4,5,6]. Immune tolerance is the specific immune suppression of a particular antigen [7]. T and B lymphocyte clone responses to a specific antigen could be tolerated with immune tolerance induction [8, 9]. This immune tolerance will recede gradually when the induction is eliminated. Current clinical ASIT is based mainly on this theory [4,5,6,7,8,9,10]
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