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Impact of Anti-Tumor Necrosis Factor (TNF) Antibodies on the T-Lymphocyte and Macrophage Cooperation in the Crohn Disease
This study is currently recruiting participants.
Verified by Centre Hospitalier Universitaire de Nice, October 2008
Sponsored by: Centre Hospitalier Universitaire de Nice
Information provided by: Centre Hospitalier Universitaire de Nice
ClinicalTrials.gov Identifier: NCT00561548
  Purpose

The aim of this research is to study in Cronh disease patients, before and after anti-TNF, the cooperation between lamina propria T-lymphocytes and macrophages, through the expression of co-signalisation molecules and their ligands, the production of cytokines participating in this cooperation, and the potential role of the regulatory T lymphocytes.


Condition Intervention
Crohn Disease
Procedure: rectosigmoïdal biopsies

Genetics Home Reference related topics: Crohn disease
MedlinePlus related topics: Crohn's Disease
Drug Information available for: Immunoglobulins Globulin, Immune Tumor Necrosis Factors
U.S. FDA Resources
Study Type: Interventional
Study Design: Basic Science, Open Label, Uncontrolled, Single Group Assignment
Official Title: Impact of Anti-TNF Antibodies on the T-Lymphocyte and Macrophage Cooperation in the Crohn Disease

Further study details as provided by Centre Hospitalier Universitaire de Nice:

Primary Outcome Measures:
  • Relative variation(%)in apoptotic cells calculated according to the formula : (% of induced apoptotic cells - % of spontaneous apoptotic cells [ Time Frame: before treatment and 10 weeks after treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • lymphocytes activation markers and macrophages activation markers [ Time Frame: before treatment and 10 weeks after treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: May 2007
Estimated Study Completion Date: April 2009
Estimated Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
A
Patients with an active Crohn disease and with azathioprine treatment
Procedure: rectosigmoïdal biopsies
rectosigmoïdal biopsies
B
Patient with an active crohn disease and without azathioprine disease
Procedure: rectosigmoïdal biopsies
rectosigmoïdal biopsies

Detailed Description:

Crohn disease is an inflammatory disease; its frequency has been increasing over the last 25 years. The physiopathology involves a failure in the negative regulatory mechanisms of the inflammatory responses in the intestines, along with an excessive production TNF-α by T-lymphocytes and macrophages of the lamina propria.

Anti-TNF-α antibodies usually give good therapeutical results, in particular in patients who are resistent or dependant on steroids. Nevertheless, in Crohn disease, the destructive T-lymphocytes - macrophages interactions, their inhibition by anti-TNFα, and the impact of these antibodies on cellular signaling remain largely unknown.

Two groups de 10 patients with an active Crohn disease, with or without azathioprine, and requiring the beginning of anti-TNF treatment are included in this study. Rectosigmoïdal biopsies and blood tests will be done before starting the treatment, and after 10 weeks of treatment. Surface antigens, cytokines and cellular molecules and the number of apoptotic cells will be analyzed by FACS, and the quantification of RNA will be analyzed by RT-PCR.

This will therefore unable us to study, before and after anti-TNF-α, in patients treated or not with azathioprine, on intestinal and blood lymphocytes, the production of cytokines involved in the lymphocyte-macrophage interaction, and the potential role of regulatory T cells.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patient older than 18
  • with social security
  • with an active Crohn disease defined by a CDAI > 250
  • with sigmoïdal and/or rectal lesions
  • requiring treatment by infliximab
  • having never received any anti-TNF treatment
  • with a negative pregnancy test for women
  • with the prescription of efficient contraception for women, having started at least a month before the beginning of the study, and throughout the duration of the study
  • accepting to participate in this research and having signed the consent form
  • not participating in any other study

Exclusion Criteria:

  • consent withdrawal
  • the stop of infliximab treatment
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00561548

Contacts
Contact: Cynthia GIRAN, CRA 04 92 03 45 89 giran.c@chu-nice.fr

Locations
France
Fédération des maladies de l'appareil digestif et de la Nutrition Recruiting
NICE, France, 06000
Contact: Xavier Hébuterne, Professor         hebuterne.x@chu-nice.fr    
Principal Investigator: Xavier Hébuterne, Professor            
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nice
Investigators
Principal Investigator: Xavier Hébuterne, Professor Centre Hospitalier Universitaire
  More Information

Publications:
Puntis J, McNeish AS, Allan RN. Long term prognosis of Crohn's disease with onset in childhood and adolescence. Gut. 1984 Apr;25(4):329-36.
Rubin GP, Hungin AP, Kelly PJ, Ling J. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther. 2000 Dec;14(12):1553-9.
Arnott ID, Watts D, Satsangi J. Azathioprine and anti-TNF alpha therapies in Crohn's disease: a review of pharmacology, clinical efficacy and safety. Pharmacol Res. 2003 Jan;47(1):1-10. Review.
ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut. 2002 Feb;50(2):206-11.
MacDonald TT, Di Sabatino A, Gordon JN. Immunopathogenesis of Crohn's disease. JPEN J Parenter Enteral Nutr. 2005 Jul-Aug;29(4 Suppl):S118-24; discussion S124-5, S184-8. Review. Erratum in: JPEN J Parenter Enteral Nutr. 2006 Jan-Feb;30(1):table of contents. DiSabatino, Antonio [corrected to Di Sabatino, Antonio].
Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994 Oct;1(7):553-62.
Noguchi M, Hiwatashi N, Liu Z, Toyota T. Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease. Gut. 1998 Aug;43(2):203-9.
Itoh J, de La Motte C, Strong SA, Levine AD, Fiocchi C. Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut. 2001 Jul;49(1):35-41.
Baert FJ, D'Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, Geboes K, Rutgeerts PJ. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology. 1999 Jan;116(1):22-8.
Filippi J, Mambrini P, Arab K, Schneider SM, Hébuterne X. [Treatment of oesophageal Crohn's disease by infliximab] Gastroenterol Clin Biol. 2005 Jan;29(1):84-5. French. No abstract available.
Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, Otsuka J, Okamura S, Fujita S, Harada M. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology. 2005 Feb;128(2):376-92.
Agnholt J, Kaltoft K. Infliximab downregulates interferon-gamma production in activated gut T-lymphocytes from patients with Crohn's disease. Cytokine. 2001 Aug 21;15(4):212-22.
Lügering A, Schmidt M, Lügering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology. 2001 Nov;121(5):1145-57.
Danese S, Sans M, Scaldaferri F, Sgambato A, Rutella S, Cittadini A, Piqué JM, Panes J, Katz JA, Gasbarrini A, Fiocchi C. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J Immunol. 2006 Feb 15;176(4):2617-24.
Filippi J, Roger PM, Schneider SM, Durant J, Breittmayer JP, Benzaken S, Bernard A, Dellamonica P, Hébuterne X; Groupe d'Etude Niçois Polyvalent en Infectiologie (GENPI). Infliximab and human immunodeficiency virus infection: Viral load reduction and CD4+ T-cell loss related to apoptosis. Arch Intern Med. 2006 Sep 18;166(16):1783-4. No abstract available.
Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, Nakamura T, Koganei K, Fukushima T, Watanabe M. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol. 2004 Sep 1;173(5):3119-30.
Kelsen J, Agnholt J, Hoffmann HJ, Rømer JL, Hvas CL, Dahlerup JF. FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease. Clin Exp Immunol. 2005 Sep;141(3):549-57.
Ochsenkühn T, Göke B, Sackmann M. Combining infliximab with 6-mercaptopurine/azathioprine for fistula therapy in Crohn's disease. Am J Gastroenterol. 2002 Aug;97(8):2022-5.
Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology. 2004 May;126(6):1593-610. Review.

Responsible Party: CHU de Nice ( Département de la Recherche Clinique et de l'Innovation )
Study ID Numbers: 06 - PP - 2006, 2006-006877-26
Study First Received: November 20, 2007
Last Updated: October 30, 2008
ClinicalTrials.gov Identifier: NCT00561548  
Health Authority: France: Afssaps - French Health Products Safety Agency;   France: French Data Protection Authority;   France: Institutional Ethical Committee

Study placed in the following topic categories:
Antibodies
Necrosis
Digestive System Diseases
Gastrointestinal Diseases
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Intestinal Diseases
Immunoglobulins

ClinicalTrials.gov processed this record on January 15, 2009