Regulatory Lymphocytes in Patients Treated With Specific Immunotherapy

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

41 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-03-31

Study Completion Date

2010-12-31

Brief Summary

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The purpose of this study is to determine whether specific subcutaneous immunotherapy affects fractions of regulatory T lymphocytes and histamine H2 receptor expression and ZAP70 in regulatory T lymphocytes.

Detailed Description

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Allergy constitutes an important problem worldwide thus effective treatment is crucial for the reduction of symptoms severity, patients' activity and quality of life as well as for the reduction of direct and indirect costs of the disease. Specific allergen immunotherapy (SIT) is a potentially curative and specific method of treatment for allergic diseases, particularly for intermittent allergic rhinitis. Specific subcutaneous immunotherapy induce peripheral tolerance and suppress inflammation in tissue. In periphery, effector T cells unresponsiveness to antigens is mediated mainly by allergen specific regulatory T cells. Regulatory T cells induced peripherally comprise IL-10 producing type 1 regulatory T cells (Tr1) and regulatory T cells subset arising in vitro from CD4+CD25- and in vivo from peripheral memory T cells whereas naturally occurring Tregs (nTregs)originate in thymus and represent about 5% of the peripheral CD4 T cells and constitutively express high levels of the high-affinity IL-2 receptor (CD25hi). They coexpress Forkhead Box Protein P3 (Foxp3), glucocorticoid induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte associated antigen (CTLA-4), and display low expression of alpha chain of the IL-7 receptor. Although clinical and immunological outcomes of SIT, that are associated with regulatory T cells functions were profoundly studied, little is known about the molecular mechanisms that are crucial for nTregs activation and function in the course of SIT. Since histamine is a key mediator in allergy that exerts its effect through 4 types of histamine receptors we decided to investigate the expression of histamine 2 receptor, that has potent immunomodulatory properties, in regulatory lymphocytes in patients treated with SIT. Furthermore, since T cell receptor activation is essential for T effector lymphocytes activation we wanted to check the expression of zeta chain associated protein (ZAP70), that constitutes a linker between TCR and lower levels of intracellular downstream signal transduction, in regulatory T cells in the course of SIT.

This is a 3-year prospective, placebo controlled, double blind trial of grass SIT. 41 patients with seasonal allergic rhinitis were randomized to receive SIT (n = 21) or placebo (n = 20) and 15 healthy were included as a control. The primary and secondary outcomes were assessed at baseline and during the treatment period - before the start of the pollen season, at the height of the pollen season and after the end of the pollen season.Results were compared between the treatment year and baseline and between the groups treated with SIT, placebo and healthy control.

Conditions

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Immunotherapy Seasonal Allergic Rhinitis

Keywords

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specific subcutaneous immunotherapy seasonal allergic rhinitis regulatory lymphocytes signal transduction histamine receptor

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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placebo

20 patients with intermittent allergic rhinitis sensitized to grass pollen allergens

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type OTHER

placebo administered with the same scheme and doses as specific subcutaneous immunotherapy

Specific subcutaneous immunotherapy

21 symptomatic patients with intermittent allergic rhinitis sensitized to grass pollen allergens

Group Type ACTIVE_COMPARATOR

Allergovit

Intervention Type DRUG

commercially available grass pollen allergoid (100%), concentration A (1000 TU/ml, therapeutic units/ml)concentration B (10000 TU/ml).Patients were given subcutaneous injections with initial dose of 0.1 ml (concentration A) was increased once a 7 (+7) days until the highest tolerated dose (0.6, concentration B) was reached and SIT was continued with injections once every 4 - 6 weeks up to two years.

Interventions

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Allergovit

commercially available grass pollen allergoid (100%), concentration A (1000 TU/ml, therapeutic units/ml)concentration B (10000 TU/ml).Patients were given subcutaneous injections with initial dose of 0.1 ml (concentration A) was increased once a 7 (+7) days until the highest tolerated dose (0.6, concentration B) was reached and SIT was continued with injections once every 4 - 6 weeks up to two years.

Intervention Type DRUG

placebo

placebo administered with the same scheme and doses as specific subcutaneous immunotherapy

Intervention Type OTHER

Other Intervention Names

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Allergovit, grass pollen 100%, Allergopharma, Germany

Eligibility Criteria

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Inclusion Criteria

* seasonal allergic rhinitis with or without allergic conjunctivitis
* sensitization to grass pollen allergens (confirmed with skin prick tests, conjunctival provocation test, specific IgE)
* symptoms of allergic rhinitis with or without conjunctivitis for at least 2 years before the study

Exclusion Criteria

* sensitization to allergens, that could interfere with grass pollen
* asthma
* cystic fibrosis
* ciliary dysmotility syndrome
* bronchiectasis
* smoking
* tuberculosis
* neoplastic disease
* chronic sinusitis and nasal polyps
* systemic glucocorticosteroids treatment
* treatment with immunotherapy in the past

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Pawel Gorski

prof, MD, PhD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Paweł Górski, Prof, MD, PhD

Role: STUDY_CHAIR

Department of Pneumonology and Allergy, Medical University of Lodz, Poland

Locations

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Department of Pneumonology and Allergy, Medical University of Lodz

Lodz, , Poland

Site Status

Countries

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Poland

References

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Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med. 2002 Jul 15;196(2):247-53. doi: 10.1084/jem.20020642.

Reference Type BACKGROUND

PMID: 12119349 (View on PubMed)

Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Semin Immunol. 2004 Apr;16(2):89-98. doi: 10.1016/j.smim.2003.12.005.

Reference Type BACKGROUND

PMID: 15036232 (View on PubMed)

Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr;4(4):330-6. doi: 10.1038/ni904. Epub 2003 Mar 3.

Reference Type BACKGROUND

PMID: 12612578 (View on PubMed)

Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003 Jan;33(1):215-23. doi: 10.1002/immu.200390024.

Reference Type BACKGROUND

PMID: 12594850 (View on PubMed)

Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62. doi: 10.1146/annurev.immunol.21.120601.141122.

Reference Type BACKGROUND

PMID: 15032588 (View on PubMed)

Jordan MS, Riley MP, von Boehmer H, Caton AJ. Anergy and suppression regulate CD4(+) T cell responses to a self peptide. Eur J Immunol. 2000 Jan;30(1):136-44. doi: 10.1002/1521-4141(200001)30:13.0.CO;2-0.

Reference Type BACKGROUND

PMID: 10602035 (View on PubMed)

Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002 Aug;3(8):756-63. doi: 10.1038/ni816. Epub 2002 Jul 1.

Reference Type BACKGROUND

PMID: 12089509 (View on PubMed)

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14;299(5609):1057-61. doi: 10.1126/science.1079490. Epub 2003 Jan 9.

Reference Type BACKGROUND

PMID: 12522256 (View on PubMed)

Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002 Jun;2(6):389-400. doi: 10.1038/nri821.

Reference Type BACKGROUND

PMID: 12093005 (View on PubMed)

Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998 Jul 20;188(2):287-96. doi: 10.1084/jem.188.2.287.

Reference Type BACKGROUND

PMID: 9670041 (View on PubMed)

Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005 Mar;22(3):329-41. doi: 10.1016/j.immuni.2005.01.016.

Reference Type BACKGROUND

PMID: 15780990 (View on PubMed)

Jutel M, Akdis M, Blaser K, Akdis CA. Mechanisms of allergen specific immunotherapy--T-cell tolerance and more. Allergy. 2006 Jul;61(7):796-807. doi: 10.1111/j.1398-9995.2006.01175.x.

Reference Type BACKGROUND

PMID: 16792576 (View on PubMed)

Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature. 2001 Sep 27;413(6854):420-5. doi: 10.1038/35096564.

Reference Type BACKGROUND

PMID: 11574888 (View on PubMed)

Liu H, Rhodes M, Wiest DL, Vignali DA. On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity. 2000 Nov;13(5):665-75. doi: 10.1016/s1074-7613(00)00066-2.

Reference Type BACKGROUND

PMID: 11114379 (View on PubMed)

Ciebiada M, Kasztalska K, Gorska-Ciebiada M, Gorski P. ZAP70 expression in regulatory T cells in allergic rhinitis: effect of immunotherapy. Clin Exp Allergy. 2013 Jul;43(7):752-61. doi: 10.1111/cea.12124.

Reference Type DERIVED

PMID: 23786282 (View on PubMed)

Other Identifiers

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1788/PO1/2007/32

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

N 402 057 32/1788

Identifier Type: -

Identifier Source: org_study_id

Regulatory Lymphocytes in Patients Treated With Specific Immunotherapy

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Study Groups

placebo

placebo

Specific subcutaneous immunotherapy

Allergovit

Interventions

Allergovit

placebo

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

Ministry of Science and Higher Education, Poland

Responsible Party

Pawel Gorski

Principal Investigators

Paweł Górski, Prof, MD, PhD

Locations

Department of Pneumonology and Allergy, Medical University of Lodz

Countries

References

Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med. 2002 Jul 15;196(2):247-53. doi: 10.1084/jem.20020642.

Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Semin Immunol. 2004 Apr;16(2):89-98. doi: 10.1016/j.smim.2003.12.005.

Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr;4(4):330-6. doi: 10.1038/ni904. Epub 2003 Mar 3.

Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003 Jan;33(1):215-23. doi: 10.1002/immu.200390024.

Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62. doi: 10.1146/annurev.immunol.21.120601.141122.

Jordan MS, Riley MP, von Boehmer H, Caton AJ. Anergy and suppression regulate CD4(+) T cell responses to a self peptide. Eur J Immunol. 2000 Jan;30(1):136-44. doi: 10.1002/1521-4141(200001)30:13.0.CO;2-0.

Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002 Aug;3(8):756-63. doi: 10.1038/ni816. Epub 2002 Jul 1.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14;299(5609):1057-61. doi: 10.1126/science.1079490. Epub 2003 Jan 9.

Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002 Jun;2(6):389-400. doi: 10.1038/nri821.

Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998 Jul 20;188(2):287-96. doi: 10.1084/jem.188.2.287.

Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005 Mar;22(3):329-41. doi: 10.1016/j.immuni.2005.01.016.

Jutel M, Akdis M, Blaser K, Akdis CA. Mechanisms of allergen specific immunotherapy--T-cell tolerance and more. Allergy. 2006 Jul;61(7):796-807. doi: 10.1111/j.1398-9995.2006.01175.x.

Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature. 2001 Sep 27;413(6854):420-5. doi: 10.1038/35096564.

Liu H, Rhodes M, Wiest DL, Vignali DA. On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity. 2000 Nov;13(5):665-75. doi: 10.1016/s1074-7613(00)00066-2.

Ciebiada M, Kasztalska K, Gorska-Ciebiada M, Gorski P. ZAP70 expression in regulatory T cells in allergic rhinitis: effect of immunotherapy. Clin Exp Allergy. 2013 Jul;43(7):752-61. doi: 10.1111/cea.12124.

Other Identifiers

1788/PO1/2007/32

N 402 057 32/1788