Tonsillar Cytokine Expression After Allergen and/or Virus Intervention

Healthy

Timothy, Influenza, Interferon, T cell, Tonsil

Hypotheses 1. Immunotherapy induces tolerogenic effects to allergens in T cell regulation in tonsils. 2. Influenza vaccination induces a strong interferon response and decreases Th2 response in tonsils. 3. Influenza vaccination as an adjuvant on immunotherapy induces a better response to immunotherapy.

Background: Tonsils are the primary nasopharyngeal lymphoid tissue and constitute the first contact point of the immune system to allergens and infectious agents. A peripheral T cell repertoire exists in tonsils, and tonsils have an active role for inducing and maintaining peripheral tolerance to allergens. Intralymphatic immunotherapy is a promising alternative for a subcutaneous or sublingual immunotherapy. More data is needed on the interaction between the peripheral (tonsillar) T cell response and specific allergen exposure and impact of respiratory virus infections on tolerance induction. Objective: To study the effects of sublingual grass pollen immunotherapy and/or nasal live attenuated influenza vaccine on tonsillar T cell and interferon (IFN) expression. In addition, we collect material on the investigation of role of tissues in immune tolerance and chronicity in allergic diseases. Patients: Human tonsil samples will be obtained from less than 30-year-old routine tonsillectomy patients after sublingual grass immunotherapy (n=30), nasal live attenuated influenza vaccine (n=30 for atopic; and n=30 for non-atopic) and immunotherapy+influenza vaccine intervention (n=30). Controls without age limit or intervention (n=580) will also be recruited. Of these, age and atopy-matched controls will be selected as comparator groups for each intervention trial (n=30 for atopic; and n=30 for non-atopic). Control group will also be used for investigation of role of tissues in immune tolerance and chronicity in allergic diseases, immunomodulatory effects of respiratory viruses main focus being on human bocavirus and human rhinovirus infections, and in the search of new respiratory viruses. Design: Study intervention products will be administered openly but the immunology outcomes will be analysed blindly. Main outcomes: Gene expressions of IFN and T cell related genes will be the main outcomes and compared between intervention groups and correlated with the number of allergen extract doses or time from nasal influenza vaccination. Systemic immunologic outcomes (in peripheral blood mononuclear cells, blood RNA expression profiles, antibodies and cytokines in serum) will also be studied. The analyses include immunogenetics, virology, bacteriology and sensitization status. Clinical symptom scores will be recorded during the next 12 months from the screening visit. Anticipated results: We expect that our tonsil approach will offer a new in vivo model for the understanding immune tolerance induction and will give new insights to the immunologic mechanisms in lymphoid tissue level. We hope to demonstrate that the immunologic effects of sublingual pollen immunotherapy can be modified with a nasal live attenuated influenza vaccine and thereby it should give basis for other add-on treatments aiming for more effective immunotherapy. The influenza virus vaccine is expected to promote Th1 cell expression over Th2 cell expression. Since the immunologic outcomes will be correlated to clinical efficacy during next influenza and pollen seasons, we hope to understand the clinical significance of the immunologic outcomes. Innovation and impact: The unique strength of the project is to answer essential questions on development of allergen tolerance and a protective vaccine response in a human in vivo situation that cannot be answered in other settings. The proposed investigations may substantially enlarge our knowledge on the pathogenesis of organ directed allergic and non-allergic inflammation in humans, because the experiments will be performed directly with disease associated human cells and tissues. We expect that novel genes and pathways of immune regulation can be identified in tonsils by a detailed investigation of human immune response development to sublingual immunotherapy and influenza vaccine. The transcriptome and epigenome of these groups and further analyses of the role of T cells, B cells and innate lymphoid cells will provide essential information particularly on differences between atopic and non-atopic individuals, and anti-vaccine responses, natural viral infection, chronic viral infection, mechanisms of hypertrophic tonsillitis versus recurrent tonsillitis. The identification of new immune tolerance and immune activation pathways involved in the regulation of tissue cells is expected to provide novel knowledge for many other diseases in addition to asthma, because dysregulated immune system activation occurs in various human disorders such as cancer, autoimmunity, transplantation rejection and chronic infections.

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