Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease

Di Sabatino A; Ciccocioppo R; Cinque B; Millimaggi D; Morera R; Ricevuti L; Cifone M G; Corazza G R
January 2004
Gut;Jan2004, Vol. 53 Issue 1, p70
Academic Journal
BACKGROUND AND AIMS: To verify whether targeting defective mucosal T cell death underlies the sustained therapeutic benefit of infliximab in Crohn''s disease, we explored its in vivo proapoptotic effect after 10 weeks of treatment, and its in vitro killing activity on lamina propria T cells (LPT) and peripheral blood T cells (PBT), both isolated from Crohn''s disease patients. METHODS: Endoscopic intestinal biopsies were collected from 10 Crohn''s disease patients (six steroid refractory and four fistulising) before and after three consecutive infusions of infliximab, administered at week 0, 2, and 6 in a single intravenous dose (5 mg/kg), and from 10 subjects who proved to have functional diarrhoea. Apoptosis was determined in vivo by TUNEL assay, and in vitro by fluorescein isothiocyanate-annexin V/propidium iodide staining on LPT and PBT from Crohn''s disease patients cultured with infliximab. The effect of the broad caspase inhibitor Z-VAD-FMK and the neutralising anti-Fas antibody ZB4 was tested in vitro on LPT and PBT treated with infliximab. Caspase-3 activity was determined by immunoblotting. RESULTS: In Crohn''s disease patients, infliximab treatment induced a sustained LPT apoptosis, still evident four weeks after the last infusion. In vitro infliximab induced death of LPT from Crohn''s disease patients occurred via apoptosis rather than necrosis. LPT showed a higher susceptibility to infliximab induced apoptosis than PBT in Crohn''s disease patients. The signalling pathway underlying the restoration of infliximab induced LPT apoptosis occurred via the caspase pathway but not Fas-Fas ligand interaction in Crohn''s disease. CONCLUSIONS: These findings demonstrate that apoptosis is the major mechanism by which infliximab exerts its killing activity on LPT in Crohn''s disease. The sustained LPT proapoptotic action of infliximab, which extends far beyond its circulating half life, may be responsible for the sustained remission induced in Crohn''s disease patients by infliximab retreatment.


Related Articles

  • Emperipolesis and cell death in NOD2-related Blau Syndrome and Crohn's disease. Janssen, Carl E. I.; Rose, Carlos D.; Naranjo, Antonio; Bader-Meunier, Brigitte; Cimaz, Rolando; Harjacek, Miroslav; Quartier, Pierre; TenCate, Rebecca; Thomee, Caroline; Cleynen, Isabelle; Martin, Tammy M.; De Hertogh, Gert; Roskams, Tania; Desmet, Valeer J.; Wouters, Carine H. // Pediatric Rheumatology;2011 Supplement, Vol. 9 Issue Suppl 1, p1 

    An abstract of the conference paper "Emperipolesis and cell death in NOD2-related Blau Syndrome and Crohn's disease," by Carlos D. Rose and colleagues is presented.

  • The Familial Mediterranean Fever (MEVF) Gene as a Modifier of Crohn's Disease. Fidder, Herma; Chowers, Yehuda; Ackerman, Zvi; Pollak, Rivka Dresner; Crusius, J. Bart. A.; Livneh, Avi; Bar-Meir, Simon; Avidan, Benjamin; Shinhar, Yael // American Journal of Gastroenterology;Feb2005, Vol. 100 Issue 2, p338 

    OBJECTIVES: Crohn's disease (CD) has been reported to be more frequent among non-Ashkenazi Jewish patients suffering from familial Mediterranean fever (FMF). Interestingly, functional similarities between the CD susceptibility gene (NOD2/CARD15) and the FMF gene (MEFV) have been described: both...

  • Infliximab: hepatosplenic T cell lymphoma.  // WHO Drug Information;2006, Vol. 20 Issue 3, p181 

    The article discusses the safety details of infliximab by Remicade. Six cases of hepatosplenic T cell lymphoma (HTSCL) in the U.S. had been reported in children and young adult patients consuming infliximab for Crohn disease, where five out of six patients died. With this report, a connection...

  • Potential therapeutic role for cytokine or adhesion molecule manipulation in Crohn's disease: in the shadow of infliximab? Shand, Alan; Forbes, Alastair // International Journal of Colorectal Disease;Jan2003, Vol. 18 Issue 1, p1 

    Background. Inappropriate activation of the intestinal immune system leading to a persistent inflammatory response is implicated in the pathogenesis of both Crohn's disease and ulcerative colitis. Various cytokines and cell surface molecules expressed by immunologically active cells are involved...

  • Infliximab linked to T-cell lymphoma in young patients.  // Reactions Weekly;3/10/2007, Issue 1142, p6 

    The article focuses on eight reports received by the Adverse Event Reporting System of the U.S. Food and Drug Administration (FDA) on hepatosplenic T-cell lymphoma (HSTCL) associated with infliximab therapy among young patients. It says that the patients were being cured for Crohn's disease. It...

  • Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Stephens, Michael C.; Shepanski, Melissa A.; Mamula, Petar; Markowitz, Jonathan E.; Brown, Kurt A.; Baldassano, Robert N. // American Journal of Gastroenterology;Jan2003, Vol. 98 Issue 1, p104 

    : ObjectivesThe published experience using infliximab (Remicade, Centocor, Malvern, PA) for the treatment of pediatric Crohn’s disease is limited but suggests utility in the treatment of refractory disease. Experience using infliximab at a large pediatric center is reviewed.: MethodsA...

  • Immunomodulators and “on demand” therapy with infliximab in Crohn’s disease: clinical experience with 400 infusions. Kinney, Timothy; Rawlins, Matthew; Kozarek, Richard; France, Renée; Patterson, David // American Journal of Gastroenterology;Mar2003, Vol. 98 Issue 3, p608 

    : ObjectivesInfliximab has been proven effective for treatment of active Crohn’s and fistulizing Crohn’s disease. We reviewed our experience with infliximab in patients with Crohn’s disease to determine if its combination with immunomodulators leads to better response and...

  • Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease Van Assche, Gert; Vanbeckevoort, Dirk; Bielen, Didier; Coremans, Georges; Aerden, Isolde; Noman, Maya; D’Hoore, Andre; Penninckx, Freddy; Marchal, Guy; Cornillie, Freddy; Rutgeerts, Paul // American Journal of Gastroenterology;Feb2003, Vol. 98 Issue 2, p332 

    : ObjectivesAlthough the clinical efficacy of infliximab as measured by closure of fistulas in Crohn’s disease has been demonstrated, its influence on the inflammatory changes in the fistula tracks is less clear. The aim of the present study was to assess the behavior of perianal fistulas...

  • Management of Crohn's disease of the ileoanal pouch with infliximab Colombel, Jean-Frederic; Ricart, Elena; Loftus Jr., Edward V.; Tremaine, William J.; Young-Fadok, Tonia; Dozois, Eric J.; Wolff, Bruce G.; Devine, Richard; Pemberton, John H.; Sandborn, William J. // American Journal of Gastroenterology;Oct2003, Vol. 98 Issue 10, p2239 

    : ObjectivesThe occurrence of Crohn''s disease (CD) in a patient with an ileal-pouch anstomosis (IPAA) often results in severe morbidity and significant chance of reservoir loss. We report our experience of the use of infliximab in these patients.: MethodsMedical records of 26 patients with an...


Read the Article


Sign out of this library

Other Topics