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

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• 作者：Oriol Juanola ; Alba Moratalla ; Ana Gutiérrez ; Laura Sempere…
• 关键词：Crohn’s disease ; FoxP3+ regulatory T cells ; Anti ; TNF ; alpha ; NOD2
• 刊名：Journal of Gastroenterology
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：50
• 期：7
• 页码：758-768
• 全文大小：888 KB
• 参考文献：1.Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417-9.PubMed View Article
  2.Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol. 1997;92:5S-1S.PubMed
  3.Obermeier F, Dunger N, Strauch UG, et al. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology. 2005;129:913-7.PubMed View Article
  4.Elson CO, Cong Y, McCracken VJ, et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206:260-6.PubMed View Article
  5.Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118-5.PubMed Central PubMed View Article
  6.Lees CW, Barrett JC, Parkes M, et al. New IBD genetics: common pathways with other diseases. Gut. 2011;60:1739-3.PubMed View Article
  7.Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603-.PubMed View Article
  8.Gutierrez A, Frances R, Amoros A, et al. Cytokine association with bacterial DNA in serum of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:508-4.PubMed View Article
  9.Gutierrez A, Holler E, Zapater P, et al. Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn’s disease is affected by NOD2/CARD15 genotype. Inflamm Bowel Dis. 2011;17:1641-0.PubMed View Article
  10.Roncarolo MG, Gregori S, Battaglia M, et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28-0.PubMed View Article
  11.Sakaguchi S, Miyara M, Costantino CM, et al. FOXP3+?regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490-00.PubMed View Article
  12.Danese S, Fiorino G, Rutella S. Regulatory T-cell therapy for Crohn’s disease: in vivo veritas. Gastroenterology. 2012;143:1135-.PubMed View Article
  13.Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295-02.PubMed Central PubMed View Article
  14.Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+?CD25+?regulatory T cells. J Immunol. 2003;170:3939-3.PubMed View Article
  15.Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+?CD4+?CD25+?and IL-10-secreting CD4+?CD25+?T cells during cure of colitis. J Immunol. 2006;177:5852-0.PubMed View Article
  16.Maul J, Loddenkemper C, Mundt P, et al. Peripheral and intestinal regulatory CD4+?CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128:1868-8.PubMed View Article
  17.Desreumaux P, Foussat A, Allez M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012;143(1207-217):e1201-.
  18.Danese S, Fiorino G, Reinisch W. Review article: causative factors and the clinical management of patients with Crohn’s disease who lose response to anti-TNF-alpha therapy. Aliment Pharmacol Ther. 2011;34:1-0.PubMed View Article
  19.Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33:987-5.PubMed View Article
  20.Dassopoulos T, Sninsky CA. Optimizing immunomodulators and anti-TNF agents in the therapy of Crohn disease. Gastroenterol Clin North Am. 2012;41:393-09.PubMed View Article
  21.Li Z, Arijs I, De Hertogh G, et al. Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm Bowel Dis. 2010;16:1299-10.PubMed View Article
  22.Boschetti G, Nancey S, Sardi F, et al. Therapy with anti-TNFalpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17:160-0.PubMed View Article
  23.Di Sabatino A, Biancheri P, Piconese S, et al. Peripheral regulatory T cells and serum transforming growth factor-beta: relationship with clinical response to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2010;16:1891-.PubMed View Article
  24.Guidi L, Felice C, Procoli A, et al. FOXP3(+) T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFalpha agents. Bio Med Res Int. 2013;2013:286368.
  25.Grundstrom J, Linton L, Thunberg S, et al. Altered immunoregulatory profile during anti-tumour necrosis factor treatment of patients with inflammatory bowel disease. Clin Exp Immunol. 2012;169:137-7.PubMed Central PubMed View Article
  26.Veltkamp C, Anstaett M, Wahl K, et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFalpha treatment. Gut. 2011;60:
• 作者单位：Oriol Juanola (1) (2)
  Alba Moratalla (1) (2)
  Ana Gutiérrez (2)
  Laura Sempere (2)
  Pedro Zapater (1) (3)
  Paula Giménez (1) (2)
  Isabel Almenta (2)
  Gloria Peiró (4)
  José M. González-Navajas (1) (2)
  José F. Such (1) (6)
  Rubén Francés (1) (2) (5)
  
  1. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
  2. Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Avda. Pintor Baeza 12, 03010, Alicante, Spain
  3. Servicio de Farmacología Clínica, Hospital General Universitario de Alicante, Alicante, Spain
  4. Servicio de Anatomía Patológica, Hospital General Universitario de Alicante, Alicante, Spain
  6. Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
  5. Dpto. Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Gastroenterology
  Oncology
  Surgical Oncology
  Hepatology
  Internal Medicine
  Colorectal Surgery
  
• 出版者：Springer Japan
• ISSN：1435-5922

文摘

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. Conclusion 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.