Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy
Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to i...
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| Published in | Journal of allergy and clinical immunology Vol. 130; no. 1; pp. 215 - 224.e7 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York, NY
Mosby, Inc
01.07.2012
Elsevier Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.
We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.
The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.
Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.
The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. |
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| AbstractList | Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. Objective We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. Methods The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Results Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores ( P < .001) and medication use scores ( P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges ( P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+ CD25high CD127low CD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. Conclusion The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. BACKGROUND: Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. OBJECTIVE: We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. METHODS: The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. RESULTS: Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG₄ levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4⁺CD25ʰⁱᵍʰCD127ˡᵒʷCD45RO⁺ forkhead box protein 3 (Foxp3)⁺ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. CONCLUSION: The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.BACKGROUNDAllergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.OBJECTIVEWe sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.METHODSThe safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.RESULTSSubjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.CONCLUSIONThe results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. Objective We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. Methods The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Results Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores ( < .001) and medication use scores ( < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges ( < .01 and < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4CD25highCD127lowCD45RO forkhead box protein 3 (Foxp3) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. Conclusion The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. Objective We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. Methods The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Results Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 andP < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+forkhead box protein 3 (Foxp3)+memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. Conclusion The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. |
| Author | Hunter, Tessa Garcia, Marco A. Reshamwala, Neha Santos, Carah B. Vissamsetti, Soujanya Hwang, Peter H. Nadeau, Kari C. Hoyte, Elisabeth G. Baroody, Fuad M. Swamy, Ravi S. |
| AuthorAffiliation | b Department of Otolaryngology, Stanford University a Division of Immunology and Allergy, Stanford University c Department of Pediatrics, Stanford University d Section of Otolaryngology–Head and Neck Surgery, University of Chicago Medical Center |
| AuthorAffiliation_xml | – name: d Section of Otolaryngology–Head and Neck Surgery, University of Chicago Medical Center – name: b Department of Otolaryngology, Stanford University – name: a Division of Immunology and Allergy, Stanford University – name: c Department of Pediatrics, Stanford University |
| Author_xml | – sequence: 1 givenname: Ravi S. surname: Swamy fullname: Swamy, Ravi S. organization: Department of Otolaryngology, Stanford University, Stanford, Calif – sequence: 2 givenname: Neha surname: Reshamwala fullname: Reshamwala, Neha organization: Department of Pediatrics, Stanford University, Stanford, Calif – sequence: 3 givenname: Tessa surname: Hunter fullname: Hunter, Tessa organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif – sequence: 4 givenname: Soujanya surname: Vissamsetti fullname: Vissamsetti, Soujanya organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif – sequence: 5 givenname: Carah B. surname: Santos fullname: Santos, Carah B. organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif – sequence: 6 givenname: Fuad M. surname: Baroody fullname: Baroody, Fuad M. organization: Section of Otolaryngology–Head and Neck Surgery, University of Chicago Medical Center, Chicago, Ill – sequence: 7 givenname: Peter H. surname: Hwang fullname: Hwang, Peter H. organization: Department of Otolaryngology, Stanford University, Stanford, Calif – sequence: 8 givenname: Elisabeth G. surname: Hoyte fullname: Hoyte, Elisabeth G. organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif – sequence: 9 givenname: Marco A. surname: Garcia fullname: Garcia, Marco A. organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif – sequence: 10 givenname: Kari C. surname: Nadeau fullname: Nadeau, Kari C. email: knadeau@stanford.edu organization: Division of Immunology and Allergy, Stanford University, Stanford, Calif |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26132817$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/22677046$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2012 American Academy of Allergy, Asthma & Immunology American Academy of Allergy, Asthma & Immunology 2015 INIST-CNRS Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. Copyright Elsevier Limited Jul 2012 2012 American Academy of Allergy, Asthma & Immunology 2012 |
| Copyright_xml | – notice: 2012 American Academy of Allergy, Asthma & Immunology – notice: American Academy of Allergy, Asthma & Immunology – notice: 2015 INIST-CNRS – notice: Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. – notice: Copyright Elsevier Limited Jul 2012 – notice: 2012 American Academy of Allergy, Asthma & Immunology 2012 |
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| Keywords | Respiratory allergies GITR SLIT Treg DM regulatory T cell GPS NDC epigenetics TG Teff CTLA-4 sublingual immunotherapy Foxp3 PD-1 Glucocorticoid-induced TNF receptor Programmed death 1 Forkhead box protein 3 Regulatory T Timothy grass Cytotoxic T-lymphocyte antigen 4 Grass pollen season CD4 + effector T Dust mite Nasal disk challenge Human Allergy Immunopathology Modification Desensitization Sublingual administration Respiratory system Immunology T-Lymphocyte Epigenetics Regulatory cell |
| Language | English |
| License | CC BY 4.0 Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. |
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| Snippet | Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.
We... Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory... Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory... BACKGROUND: Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory... |
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| SubjectTerms | Administration, Sublingual Adult adults allergens Allergens - immunology Allergies Allergy and Immunology Animals Asthma Biological and medical sciences Bronchi - cytology Bronchi - immunology Child Child, Preschool children Cytokines - metabolism Dermatophagoides Desensitization, Immunologic - methods DNA methylation Double-Blind Method drug therapy Dust - immunology dust mites epigenetics Epigenomics Epithelial Cells - immunology Female Fundamental and applied biological sciences. Psychology Fundamental immunology Gene expression Humans hypersensitivity immunoglobulin E immunoglobulin G Immunopathology immunotherapy Interleukin-1 - metabolism loci Lymphocytes Male Mast Cells - immunology Medical sciences Mites - immunology nose patients Phleum - immunology Phleum pratense placebos regulatory T cell Respiratory allergies Rhinitis, Allergic, Seasonal - immunology Rhinitis, Allergic, Seasonal - therapy Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis sublingual immunotherapy T-lymphocytes T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism Th2 Cells - immunology Treatment Outcome |
| Title | Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy |
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