title: Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with Crohn's disease.
abstract: BACKGROUND
  Anti-TNF-α therapies interact with the tolerogenic response in patients with Crohn's disease, modulating inflammation. However, drug levels and the genetic background may affect this interaction.
  
  
  METHODS
  Patients with Crohn's disease in remission on biologic monotherapy were enrolled in this study. FoxP3+ lymphocytes, NOD2 genotype, serum cytokine, anti-TNF-α levels, and anti-drug antibodies were evaluated. Regulatory T cell response to infliximab was evaluated in vitro.
  
  
  RESULTS
  Fifty-seven patients were included. Thirty-nine patients (68.4%) were receiving non-intensified biologic therapy whereas 18 patients (31.6%) were under an intensified biologic schedule due to loss of response. Eleven intensified patients (61.1%) showed a variant NOD2 genotype vs 9 on non-intensified biologics (23%, p < 0.01). Percentage of FoxP3+ T cells and serum free anti-TNF-α levels were significantly higher in patients with a wild-type vs variant NOD2 genotype, either under non-intensified or intensified schedule. Increasing amounts of infliximab significantly increased the expression of FoxP3+ T cells and anti-TNF-α levels in the supernatant from wild-type NOD2 patients cultured cells whereas the induction of FoxP3+ T cells and anti-TNF-α levels in the supernatant from variant NOD2 patients cultured cells were significantly lower. TNF-α and IL-10 showed a correlation with the FoxP3+ T cell population percentage and serum levels of anti-TNF-α, irrespective of NOD2 genotype. Eight variant NOD2 patients (66.6%) vs 4 wild-type NOD2 patients (8.8%) showed a perianal phenotype (p = 0.01). A significant reduction of the percentage of FoxP3+ T cells and serum levels of anti-TNF-α was observed in patients with the associated perianal disease.
  
  
  CONCLUSIONS
  Anti-TNF-α loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with CD.
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Juanola
authors.forename: Alba
authors.initials: A
authors.lastname: Moratalla
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez
authors.forename: Laura
authors.initials: L
authors.lastname: Sempere
authors.forename: Pedro
authors.initials: P
authors.lastname: Zapater
authors.forename: Paula
authors.initials: P
authors.lastname: Giménez
authors.forename: Isabel
authors.initials: I
authors.lastname: Almenta
authors.forename: Gloria
authors.initials: G
authors.lastname: Peiró
authors.forename: José M
authors.initials: JM
authors.lastname: González-Navajas
authors.forename: José F
authors.initials: JF
authors.lastname: Such
authors.forename: Rubén
authors.initials: R
authors.lastname: Francés
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004247:DNA / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005765:Gastrointestinal Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D000069285:Infliximab; D000068879:Adalimumab