title: Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation.
abstract: BACKGROUND
  Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen-induced rhinoconjunctivitis. This immunotherapy downregulates TH2 immune responses, induces tolerogenic pathways, and increases regulatory T cells. However, associated immune response markers of allergen desensitization remain undefined.
  
  
  OBJECTIVE
  We sought to characterize the kinetics of individual changes in the immunologic response to grass tablet SLIT.
  
  
  METHODS
  We evaluated the systemic effects of SLIT in a longitudinal analysis of humoral and cellular immune parameters in peripheral blood samples.
  
  
  RESULTS
  Grass tablet SLIT administration induced a 2-phase systemic humoral and cellular response. The TH2 response was initially exacerbated and detected as increased allergen-specific IgE (sIgE) and IgG4 (sIgG4) levels and an increase in IL-4-producing cells, followed by downregulation of the TH2 response with a shift toward a TH1 cytokine profile. T cells with a regulatory phenotype were also elicited. Statistical correlations between immunologic measurements for each patient throughout therapy indicated that TH2 response downregulation and reduction of the immediate SLIT-induced IgE response were associated with increased allergen-specific IgG4 synthesis early in therapy. TH2 response downregulation by month 4 correlated with increased frequency of CD4(+) T cells with a regulatory phenotype by 12 months.
  
  
  CONCLUSIONS
  Changes in sIgE levels after therapy were linked to a specific IgG4 response, and production of blocking antibodies correlated with TH2 response downregulation. Reduced IL-4(+) cell frequency was linked to an increase in the frequency of CD4(+) T cells with a regulatory phenotype. Changes in sIgE levels and reduced IL-4 and blocking antibody levels could thus be used as indicators of a patient's immune response to therapy.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Suárez-Fueyo
authors.affiliation: Servicio de Alergia, Hospital Universitario de La Princesa (IP), Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Ramos
authors.affiliation: Departamento de I+D, ALK-Abelló, Madrid, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Galán
authors.affiliation: Departamento de I+D, ALK-Abelló, Madrid, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Jimeno
authors.affiliation: Department of Immunology, ALK-Abelló, Hørsholm, Denmark.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wurtzen
authors.affiliation: Departamento de I+D, ALK-Abelló, Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Marin
authors.affiliation: Servicio de Alergia, Hospital Universitario de La Princesa (IP), Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Consolación
authors.initials: C
authors.lastname: de Frutos
authors.affiliation: Servicio de Alergia, Hospital Universitario de La Princesa (IP), Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Blanco
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
authors.affiliation: Departamento de I+D, ALK-Abelló, Madrid, Spain.
authors.forename: Domingo
authors.initials: D
authors.lastname: Barber
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain. Electronic address: rvarona@cnb.csic.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Varona
mesh_terms: D000328:Adult; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D056747:Immunomodulation; D015847:Interleukin-4 / Q000378:metabolism; D031784:Phleum / Q000276:immunology*; D010936:Plant Extracts / Q000627:therapeutic use*; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy* / Q000276:immunology; D063729:Sublingual Immunotherapy / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013607:Tablets; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: C551013:Grazax; D007074:Immunoglobulin G; D010936:Plant Extracts; D013607:Tablets; D015847:Interleukin-4; D007073:Immunoglobulin E
keywords: Allergen-specific IgE; Allergen-specific IgG; CTLA-4; Cytotoxic T lymphocyte–associated antigen 4; GPS; Grass pollen season; IL-4; IgE; IgE-FAB; IgE-facilitated antigen binding; IgG(4); Induced regulatory T; Regulatory T; SLIT; Sublingual immunotherapy; Treg; allergic rhinitis; iTreg; regulatory T cells; sIgE; sIgG