Regulatory Lymphocytes in Patients Treated With Specific Immunotherapy

Immunotherapy Clinical Trial

Official title:

Regulatory Lymphocytes (Treg) in the Modulation of Allergic Inflammation in Patients Treated With Specific Immunotherapy.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01475188
• Other study ID #: N 402 057 32/1788
• Secondary ID: 1788/PO1/2007/32
• Status: Completed
• Phase: Phase 4
• First received: November 16, 2011
• Last updated: November 18, 2011
• Start date: March 2007
• Est. completion date: December 2010

Study information

• Verified date: November 2011
• Source: Ministry of Science and Higher Education, Poland
• Contact: n/a
• Is FDA regulated: No
• Health authority: Poland: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: December 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Immunotherapy
• Rhinitis, Allergic, Seasonal
• Seasonal Allergic Rhinitis

Intervention

Drug:
• 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.

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

Locations

Country	Name	City	State
Poland	Department of Pneumonology and Allergy, Medical University of Lodz	Lodz

Sponsors (1)

Lead Sponsor	Collaborator
Ministry of Science and Higher Education, Poland

Country where clinical trial is conducted

Poland, 

References & Publications (14)

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. Epub 2002 Jul 1. — View Citation

Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Semin Immunol. 2004 Apr;16(2):89-98. Review. — View Citation

Cao D, Malmström 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. — View Citation

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. Erratum in: J Exp Med 2002 Aug 19;196(4):559. J Exp Med 2002 Sep 16;196(6):867. — View Citation

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. Epub 2003 Mar 3. — View Citation

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. — View Citation

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. Epub 2003 Jan 9. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002 Jun;2(6):389-400. Review. — View Citation

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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	numbers of regulatory T lymphocytes (nTregs)	Numbers of regulatory T cells (nTregs) at baseline year both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen season and in the 2nd year of immunotherapy both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen.	Change from the baseline year to the 2nd year of immunotherapy.	No
Secondary	Expression of zeta chain associated protein (ZAp70) in regulatory lymphocytes (nTregs)	Expression of zeta chain associated protein (ZAP70) in regulatory T cells (nTregs) at baseline year both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen season and in the 2nd year of immunotherapy both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen.	Change from the baseline year to the 2nd year of immunotherapy	No
Secondary	Expression of histamine H2 receptor in regulatory lymphocytes (NTregs)	Expression of histamine H2 receptor in regulatory T cells (nTregs) at baseline year both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen season and in the 2nd year of immunotherapy both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen.	Change from the baseline year to the second year of immunotherapy	No
Secondary	Rhinoconjunctivitis symptom score	Change of the rhinoconjunctivitis symptoms score from the baseline year to the 2nd year of immunotherapy	Change from the baseline year to the second year of immunotherapy	No
Secondary	Nasal eosinophilia	Numbers of eosinophils in nasal lavage during the baseline year both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen season and in the 2nd year of immunotherapy both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen.	Change from the basline year to the 2nd year of immunotherapy	No
Secondary	Concentration of nitric oxide in exhaled air	Concentration of nitric oxide in exhaled air during the baseline year both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen season and in the 2nd year of immunotherapy both 6 weeks before the start of the pollen season, at the height of pollen season and 6 weeks after the termination of the pollen.	Change from the baseline year to the 2nd year of immunotherapy	No
Secondary	Consumption of rescue medications	Comparison of the rescue medication intake during the baseline year and during the treatment	Change from the baseline year to the second year of imunotherapy	No