Impact of Anti-Tumor Necrosis Factor (TNF) Antibodies on the T-lymphocyte and Macrophage Cooperation in Crohn Disease

Crohn Disease Clinical Trial

Official title:

Impact of Anti-TNF Antibodies on the T-lymphocyte and Macrophage Cooperation in the Crohn Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00561548
• Other study ID #: 06 - PP - 2006
• Secondary ID: 2006-006877-26
• Status: Terminated
• Phase: N/A
• First received: November 20, 2007
• Last updated: May 27, 2011
• Start date: May 2007
• Est. completion date: April 2009

Study information

• Verified date: February 2009
• Source: Centre Hospitalier Universitaire de Nice
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: French Data Protection AuthorityFrance: Institutional Ethical Committee
• Study type: Interventional

Clinical Trial Summary

The aim of this research is to study Crohn 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 regulatory T lymphocytes.

Description:

Crohn disease is an inflammatory disease and 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 of TNF-α by T-lymphocytes and macrophages of the lamina propria.

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

Two groups of 10 patients with active Crohn disease, with or without azathioprine, and requiring the start 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 enable 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: April 2009
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• patient older than 18

• social security

• active Crohn disease defined by a CDAI > 250

• sigmoïdal and/or rectal lesions

• requiring treatment by infliximab

• having never received any anti-TNF treatment

• a negative pregnancy test for women

• prescription of efficient contraception for women, having started at least a month before beginning the study, and throughout the duration of the study

• acceptance to participate in this research and having signed the consent form

• not participating in any other study

Exclusion Criteria:

• consent withdrawal

• the halt of infliximab treatment

Study Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Procedure:
• rectosigmoïdal biopsies
rectosigmoïdal biopsies

Locations

Country	Name	City	State
France	Fédération des Maladies de l'appareil Digestif et de la Nutrition	Nice

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nice

Country where clinical trial is conducted

France, 

References & Publications (19)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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]. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology. 2004 May;126(6):1593-610. Review. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative variation (%) in apoptotic cells calculated according to the formula: (% of induced apoptotic cells) - (% of spontaneous apoptotic cells)		before treatment and 10 weeks after treatment	Yes
Secondary	Lymphocyte activation markers and macrophage activation markers		before treatment and 10 weeks after treatment	No