Tonsillar Cytokine Expression After Allergen and/or Virus Intervention (Tons2)

April 20, 2016 updated by: Tuomas Jartti, Turku University Hospital

T Cell and Interferon Expression in Tonsils After Sublingual Immunotherapy and/or Nasal Live Attenuated Influenza Vaccine

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

180

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Pori, Finland, 28500
        • Not yet recruiting
        • Department of Otorhinolaryngology, Satakunta Central Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Antti Silvoniemi, M.D.
        • Sub-Investigator:
          • Kirsi Ylitalo, M.D.
      • Salo, Finland, 24130
        • Recruiting
        • Department of Otorhinolaryngology, Salo Regional Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Antti Silvoniemi, M.D.
      • Turku, Finland, 20521
        • Recruiting
        • Department of Otorhinolaryngology, Turku University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Tuomo Puhakka, M.D.
        • Sub-Investigator:
          • Antti Silvoniemi, M.D.
      • Turku, Finland, 20521
        • Recruiting
        • Department of Pediatrics, Turku University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Tuomas Jartti, M.D.
        • Sub-Investigator:
          • Varpu Elenius, M.D.
        • Sub-Investigator:
          • Maria Saarinen, M.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • elective tonsillectomy with or without adenotomy according to clinical indication
  • age >4 and <30 years
  • written informed consent from the study subject or his/her guardian
  • Fluenz® will be used for ages >4 and <30 years, i.e. off-label use of ages >18 and <30 years

Exclusion Criteria:

  • systemic anti-inflammatory medication within prior 4 weeks
  • systemic diseases affecting the immune system e.g. autoimmune diseases, immune complex diseases or immune deficiency diseases other than allergy, asthma or atopic dermatitis
  • malignancy, depression, psychiatric illness or medication; planned vaccination during the study period (vaccinations should not be given during study period)
  • forced expiratory volume in 1 second (FEV1) is under 80% of normal value or asthma is in a bad balance for those patients who would participate in the immunotherapy
  • sublingual grass pollen will not be given for children under the age of 5
  • additional exclusion criteria for Grazax® include hypersensitivity to any of the excipients (gelatin [fish source], mannitol, sodium hydroxide), inflammatory conditions in the oral cavity with severe symptoms such as oral lichen planus with ulcerations or severe oral mycosis, patients with uncontrolled or severe asthma (in adults: FEV1 < 70% of predicted value after adequate pharmacologic treatment, in children: FEV1 < 80% of predicted value after adequate pharmacologic treatment)
  • addition exclusion criteria for Fluenz® include hypersensitivity to the active substances, to any of the excipients (sucrose, dibasic potassium phosphate, monobasic potassium phosphate, gelatin [porcine, Type A], arginine hydrochloride, monosodium glutamate monohydrate, gentamicin [a possible trace residue], eggs or to egg proteins [e.g. ovalbumin] and children and adolescents younger than 18 years of age receiving salicylate therapy because of the association of Reye's syndrome with salicylates and wild-type influenza infection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Timothy
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) (n=30) .
Biological: Live attenuated influenza virus
Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=60, 50:50 atopic:non-atopic).
Procedure: Timothy + attenuated influenza virus
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) + Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=30).
Active Comparator: Live attenuated influenza virus
Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=60, 50:50 atopic:non-atopic).
Procedure: Timothy + attenuated influenza virus
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) + Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=30).
Biological: Timothy, Phleum pretense
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) (n=30) .
Active Comparator: Timothy + attenuated influenza virus
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) + Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=30).
Biological: Live attenuated influenza virus
Virus. Fluenz®, nasal live attenuated influenza vaccine, one 0.2 mL dose (MedImmune, Gaithersburg, USA) (n=60, 50:50 atopic:non-atopic).
Biological: Timothy, Phleum pretense
Allergen. Grazax® sublingual 75.000 SQ-T tablet (extracted from timothy, Phleum pretense), once daily until operation (ALK-Abelló, Hørsholm, Denmark) (n=30) .
No Intervention: No intervention
No intervention (n=60, 50:50 atopic:non-atopic).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Expressions of interferon and T cell and closely related cytokines and transcription factors in tonsils.
Time Frame: Up to 3 years
Expressions of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2 and Tbet will be analyzed by quantitative real-time PCR.
Up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Turku University Hospital

Collaborators

Academy of Finland
Juselius Foundation, Helsinki, Finland
Foundation for Paediatric Research, Finland
EVO special government transfers, Turku, Finland

Investigators

  • Principal Investigator: Tuomas Jartti, M.D., Dept of Pediatrics, Turku University Hospital, Turku, Finland.
  • Principal Investigator: Cezmi Akdis, M.D., prof, Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2013

Primary Completion (Anticipated)

September 1, 2016

Study Completion (Anticipated)

September 1, 2016

Study Registration Dates

First Submitted

August 10, 2013

First Submitted That Met QC Criteria

August 15, 2013

First Posted (Estimate)

August 16, 2013

Study Record Updates

Last Update Posted (Estimate)

April 21, 2016

Last Update Submitted That Met QC Criteria

April 20, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • Tons2

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Healthy

Clinical Trials on Live attenuated influenza virus

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Papua New Guinea

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe