The influence of viral infection on therapeutic immune tolerance in allergic airways disease.
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Inflammation Research
Abstract
Allergic airways disease such as asthma is rising in children. Allergy can be triggered by different environmental allergens (e.g. pollen). In susceptible children, inhaling allergens may cause allergic reactions with breathing problems, sometimes requiring hospital treatment. Treatment with small allergen fragments, called peptide-based immunotherapy (PIT), can render allergic patients tolerant, i.e. unresponsive to their allergen, without the risk of allergic reactions. How tolerance to allergen develops is not fully understood.
Children commonly suffer from viral infections such as the common cold and can sometimes develop allergic airways disease thereafter. Why this happens is unclear, but it is thought that viral infections interfere with the immune cells that maintain tolerance. Thus, there is concern that PIT may be ineffective or even detrimental if it coincides with a viral infection. Using a mouse model, I will study how immune cells contribute to the development of tolerance following PIT. I will then determine the effects of viral infection both on these cells and on the ability of PIT to induce tolerance. Understanding these interactions is vital if PIT is to be used safely in treating children with allergy. In addition, my studies will further our understanding of the mechanisms underlying virus induced allergy.
Children commonly suffer from viral infections such as the common cold and can sometimes develop allergic airways disease thereafter. Why this happens is unclear, but it is thought that viral infections interfere with the immune cells that maintain tolerance. Thus, there is concern that PIT may be ineffective or even detrimental if it coincides with a viral infection. Using a mouse model, I will study how immune cells contribute to the development of tolerance following PIT. I will then determine the effects of viral infection both on these cells and on the ability of PIT to induce tolerance. Understanding these interactions is vital if PIT is to be used safely in treating children with allergy. In addition, my studies will further our understanding of the mechanisms underlying virus induced allergy.
Technical Summary
Aims and objectives:
Respiratory allergy including asthma is an increasing problem in children. Immunotherapy with allergen protein is used to induce tolerance but poses the risk of severe allergic reactions including anaphylaxis due to IgE binding. Peptide-based immunotherapy (PIT) may convey T cell tolerance without providing IgE binding epitopes, thus negating the risk of anaphylaxis. The exact mechanisms of PIT and the impact of concomitant viral infections on tolerance induction are not known.
This project will investigate how tolerance induced by PIT is influenced by concomitant viral infection. Extending an existing ovalbumin (OVA)-specific, transgenic, CD4+ T cell receptor mouse (OT-II) model of PIT into an allergic airways disease setting, we will assess the contribution of foxp3+ regulatory T cells (Treg) to the development of tolerance. Whether tolerance can be induced and maintained during an ongoing respiratory viral infection will be determined.
Design: We will utilise a murine model of allergic airways disease induced by intraperitoneal sensitization to OVA/alum followed by intratracheal OVA challenges. Tolerance will be induced using intravenous OVA-peptide either prophylactically (before sensitisation) or therapeutically (after sensitization). Respiratory syncytial virus (RSV) infection prior to or following PIT will reveal the impact of infection on development and maintenance of allergen tolerance.
Methods: Airway inflammation and immune activation will be demonstrated by lung histology, T cell activation studies and assessment of OVA-specific antibody levels. Transfer of OT-II T cells will enable precise analysis of dendritic cell and T cell functions and phenotype during sensitisation, PIT and RSV-infection, allowing analysis of co-stimulatory molecules and cytokine production. Foxp3-reporter mice will enable assessment of expansion or conversion of Tregs in these studies.
Scientific and medical opportunities: PIT is an attractive treatment approach for allergic diseases. Limited human trials have produced promising, yet unpredictable results in part due to incomplete understanding of the immune mechanisms behind PIT. This project offers important scientific opportunities for further clarification of the mechanisms leading to immune tolerance in PIT.
Viral infections are known to enable sensitization to non-immunogenic antigens and are thought to facilitate the development of allergic childhood asthma. Thus, it seems possible that PIT in children may be ineffective or even detrimental if complicated by viral infection. This study will help clarify the influence of viral infection on PIT. Such knowledge is required if PIT is to be used safely in children in the future.
Respiratory allergy including asthma is an increasing problem in children. Immunotherapy with allergen protein is used to induce tolerance but poses the risk of severe allergic reactions including anaphylaxis due to IgE binding. Peptide-based immunotherapy (PIT) may convey T cell tolerance without providing IgE binding epitopes, thus negating the risk of anaphylaxis. The exact mechanisms of PIT and the impact of concomitant viral infections on tolerance induction are not known.
This project will investigate how tolerance induced by PIT is influenced by concomitant viral infection. Extending an existing ovalbumin (OVA)-specific, transgenic, CD4+ T cell receptor mouse (OT-II) model of PIT into an allergic airways disease setting, we will assess the contribution of foxp3+ regulatory T cells (Treg) to the development of tolerance. Whether tolerance can be induced and maintained during an ongoing respiratory viral infection will be determined.
Design: We will utilise a murine model of allergic airways disease induced by intraperitoneal sensitization to OVA/alum followed by intratracheal OVA challenges. Tolerance will be induced using intravenous OVA-peptide either prophylactically (before sensitisation) or therapeutically (after sensitization). Respiratory syncytial virus (RSV) infection prior to or following PIT will reveal the impact of infection on development and maintenance of allergen tolerance.
Methods: Airway inflammation and immune activation will be demonstrated by lung histology, T cell activation studies and assessment of OVA-specific antibody levels. Transfer of OT-II T cells will enable precise analysis of dendritic cell and T cell functions and phenotype during sensitisation, PIT and RSV-infection, allowing analysis of co-stimulatory molecules and cytokine production. Foxp3-reporter mice will enable assessment of expansion or conversion of Tregs in these studies.
Scientific and medical opportunities: PIT is an attractive treatment approach for allergic diseases. Limited human trials have produced promising, yet unpredictable results in part due to incomplete understanding of the immune mechanisms behind PIT. This project offers important scientific opportunities for further clarification of the mechanisms leading to immune tolerance in PIT.
Viral infections are known to enable sensitization to non-immunogenic antigens and are thought to facilitate the development of allergic childhood asthma. Thus, it seems possible that PIT in children may be ineffective or even detrimental if complicated by viral infection. This study will help clarify the influence of viral infection on PIT. Such knowledge is required if PIT is to be used safely in children in the future.