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PubMed2001

Novel Helicobacter species isolated from rhesus monkeys with chronic idiopathic colitis.

Chronic, idiopathic diffuse colitis is a well recognised clinical and pathological entity in captive rhesus monkeys. Six rhesus monkeys were diagnosed with clinically debilitating, chronic diarrhoea. Histologically, colonic tissues were characterised as chronic, moderate to severe colitis and typhlitis, with diffuse mononuclear inflammation of lamina propria, reactive lymphoid hyperplasia and multifocal micro-abscesses. Colonic tissues were cultured for Salmonella spp. and Shigella spp.; all results were negative. Samples were negative for Clostridium difficile A and B toxins, and special stains of colonic tissue for acid-fast bacteria were also negative. The six diarrhoeic monkeys tested gave negative results for serum IgG antibodies to herpes B virus, STLV, SRV and SIV. Colonic tissue from the six diarrhoeic and two clinically normal monkeys with histologically confirmed colitis from the same colony were also subjected to micro-aerobic culture. Micro-aerobic cultures from all eight monkeys incubated at 37 degrees C and 42 degrees C revealed pinpoint or spreading colonies on antibiotic-containing media. Bacteria were identified as gram-negative, oxidase positive and urease negative. Of the nine strains characterised biochemically, two separate biotypes (corresponding to different species by 16S rRNA analysis) were identified. One biotype (type 1), from non-diarrhoeic monkeys and the second biotype (type 2) from diarrhoeic animals with subclinical chronic colonic inflammation, differed by catalase activity, ability to reduce nitrate to nitrite and sensitivity to cephalothin. Complete 16S rRNA analysis of five of the nine strains characterised biochemically indicated that the organisms isolated were two novel Helicobacter spp. By electron microscopy, these novel helicobacters had spiral morphology with bipolar sheathed flagella. This is the first report describing the isolation of novel Helicobacter spp. from inflamed colons of rhesus monkeys. Studies are needed to determine whether these novel Helicobacter spp. play a causal role in the initiation and progression of chronic colitis in macaques. Further microbiological and histological analysis of this chronic idiopathic colitis syndrome in macaques may prove useful in understanding the aetiology and pathogenesis of inflammatory bowel disease in man.

Animals↗
PubMed1976

Salmonella typhimurium colitis.

A patient in whom Salmonella typhimurium infection caused a localised colitis is described. Colitis has been demonstrated in experimental animals infected with S. typhimurium and noted at post mortem in patients dying from S. typhimurium infection. However colitis is an infrequently recognised feature of this infection in man, the usual diagnosis being one of gastroenteritis. There have been four other cases reported with radiological evidence of colonic involvement due to salmonella infection. Colitis probably occurs more frequently than is usually recognised in this condition and must be distinguished from ulcerative colitis.

Adult↗
PubMed2004

Decreased availability of intestinal dopamine in transmural colitis may relate to inhibitory effects of interferon-gamma upon L-DOPA uptake.

AIMS: The present study aimed to evaluate the relationship between intestinal inflammation, interferon-gamma (IFN-gamma) levels and intestinal levels of dopamine, its precursor l-3,4-dihydroxyphenylalanine (L-DOPA), and the activity of aromatic L-amino acid decarboxylase (AADC) activity along the digestive tract in a rat experimental model of colitis. METHODS: Colitis was induced by rectal administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS). Catechol derivatives were assayed by means of HPLC-EC. RESULTS: It is shown that dopamine and noradrenaline levels in the distal colon (inflamed mucosa), but not in the ileum (non-inflamed mucosa), of TNBS-treated rats were markedly lower than in control animals. A slight decrease in L-DOPA tissue levels, no changes in AADC activity and an increase in plasma IFN-gamma levels accompanied this decrease in dopamine levels. Exposure of Caco-2 cells, a human intestinal epithelial cell line, to human IFN-gamma resulted in a concentration-dependent and long-lasting inhibition of L-DOPA uptake, which most likely explains the decrease in dopamine levels in the inflamed mucosa. CONCLUSION: Changes in tissue levels of noradrenaline and dopamine in experimental colitis in the rat follow a similar pattern to that observed in patients with Crohn's disease and ulcerative colitis. In this model of experimental colitis, the decrease in dopamine levels is most likely explained by the inhibitory effect of IFN-gamma on L-DOPA uptake by intestinal epithelial cells.

Animals↗
PubMed1990

Immune complex induced experimental colitis: beneficial effect of sulphasalazine in rabbits.

Experimental colitis was induced in rabbits by exposing the colon mucosa to 1% formalin followed by i.v. injections of soluble immune complexes made with antigen in excess. The animals were preimmunized with Escherichia coli O14:K7:H--inducing antibodies cross-reactive to intestinal epithelium. Animals with this colitis were divided in two groups. One group was treated with sulphasalazine and the other was given vehicle only. Sulphasalazine was administered daily at 125.5 mumol (50 mg) per kg body weight. The administration was started at the same day as the colitis was initiated. At Day 6, 13 and 30 following induction of colitis, biopsies were sampled and histologically evaluated. Inflammation was assessed by scores for inflammatory cells, crypt distortion, decreased crypt number and presence of crypt abscesses, thus corresponding to the picture seen in humans. A statistically significant lower score of inflammation was seen on Day 6 and 13 (P less than 0.01) and on Day 30 (P less than 0.05) following induction of colitis in animals treated with sulphasalazine.

Animals↗
PubMed1994

Mesalamine capsules enhance the quality of life for patients with ulcerative colitis.

Patients with ulcerative colitis tend to be young, potentially at peak lifetime productivity levels, and the disease can be devastating in its effects on the quality of life in these individuals. No treatment for ulcerative colitis can be comprehensively evaluated without careful attention to its impact on such psychosocial issues. The quality of life was evaluated in 374 ulcerative colitis patients using mesalamine capsules at 1 g, 2 g, and 4 g daily versus placebo in an 8-week, randomized, dose-response, placebo-controlled, double-blind, multicentre trial. Function-related quality of life parameters were assessed in this study, including five pertinent clinical symptoms and seven general life capabilities. These parameters have been previously shown to be valid, reliable, and responsive to the disease activity of ulcerative colitis. All of the parameters were recorded using a 10-cm visual analogue scale, except trips to the toilet which were recorded in patients' diaries. The mean change was calculated from baseline and endpoint data. Mesalamine at 2 g and 4 g daily was significantly superior to placebo in improving each of the 12 quality of life parameters (P < 0.05). These results indicate that controlled-release mesalamine significantly enhances the quality of life for patients with either left-sided ulcerative colitis or pancolitis.

Administration, Oral↗
PubMed1995

Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis.

BACKGROUND: To summarize and quantify the evidence supporting rectal 5- or 4-aminosalicylate (ASA) therapies for disease exacerbation or remission maintenance in distal ulcerative colitis, we performed a meta-analysis. METHODS: All randomized, double-blind controlled trials involving aminosalicylate therapy were retrieved from a MEDLINE search, review articles on ulcerative colitis therapy or their bibliographies. Of 55 studies retrieved, 19 met the inclusion criteria. Appraisal and data extraction were performed by two observers and scoring disagreements were resolved by consensus. RESULTS: Eleven trials tested 5-ASA and three tested 4-ASA in active ulcerative colitis. 5-ASA was superior to placebo for inducing remission or symptomatic improvement in active ulcerative colitis with a pooled odds ratio of 7.36 (95% Confidence interval (CI): 4.72-11.47). In four trials the pooled odds ratio for endoscopic improvement was 10.04 (95% CI: 5.72-17.61) and for histological improvement 10.31 (95% CI: 5.85-18.18). Studies evaluating 4-ASA suggest a benefit similar to prednisolone in treating active disease. Five trials assessed remission maintenance with 5-ASA, and when compared to placebo gave a pooled odds ratio of 16.22 (95% CI: 4.71-55.92). No dose-response relationship was observed. ASA compounds were not therapeutically superior to other treatments. CONCLUSIONS: We conclude that rectal 5-ASA is effective therapy for active distal ulcerative colitis. More trials are needed to assess 4-ASA, dose-response effects and the ideal regimen for remission maintenance.

Administration, Rectal↗
PubMed2004

Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid-dependent ulcerative colitis.

BACKGROUND: The efficacy of azathioprine in the management of steroid-dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid-dependent and refractory patients. AIM: To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid-dependent ulcerative colitis. METHODS: Survey of 34 patients with steroid-dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year. RESULTS: Mean age was 39.1 +/- 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52-84%) and 72.7%, as per protocol (confidence interval 95%: 54-86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated. CONCLUSIONS: Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid-dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.

Adult↗
PubMed2004

Review article: the management of mild to severe acute ulcerative colitis.

The goals for the management of acute ulcerative colitis are the objective evaluation of disease activity, induction of remission, prevention of relapse and treatment of complications. Clinical practice should be guided by simple activity indices, as it is easy to underestimate severity. For the induction of remission, topical treatment with mesalazine (mesalamine) is appropriate initial therapy for distal disease but, if symptoms persist for over a fortnight, decisive treatment is usually appreciated by the patient. For mild to moderate disease, corticosteroids have been the mainstay in Europe, although high-dose aminosalicylates (such as Pentasa, 4 g orally daily and 1 g rectally) are an alternative for symptoms not interfering with daily activity. Novel therapeutic approaches in ulcerative colitis have lagged behind those used for Crohn's disease, but several (epidermal growth factor, RDP 58, basiliximab, leucocytapheresis) are on the horizon. Severe colitis, defined as a bloody stool frequency of more than six per day with any one of tachycardia (pulse > 90 beats/min), temperature (> 37.8 degrees C), anaemia (haemoglobin < 10.5 g/dL) or raised erythrocyte sedimentation rate (> 30 mm/h), is an indication for intensive intravenous treatment. National UK figures indicate that 30% of ulcerative colitis cases progress to colectomy, and objective criteria for predicting the need for colectomy have been validated. The timing of colectomy is the most important decision that a physician is called upon to make, in conjunction with the patient and surgical colleagues. For the maintenance of remission, aminosalicylates continue to be first-line therapy, although the choice of 5-aminosalicylate appears to be influenced as much by geography as by theoretical considerations. Steroids have no place in the maintenance of remission. Indications for azathioprine include patients after a severe relapse of ulcerative colitis, those with early relapse after steroids (dose of < 15 mg/day, or within 6 weeks of stopping) and those needing a second course of steroids within a year. Therapeutic decisions should have a strategy, aimed at navigating the patient around relapses and through to sustained remission. Good management depends on clinical skills, compassion and care of the individual, in addition to pharmaceuticals.

Acute Disease↗
PubMed2004

Meta-analysis: budesonide treatment for collagenous colitis.

BACKGROUND: Collagenous colitis is typified by chronic watery diarrhoea and characteristic histological alterations of the colonic mucosa without endoscopic abnormalities. Budesonide, a corticosteroid with high first-pass metabolism has been examined in collagenous colitis, but studies to date have had small numbers, and relatively low statistical power. AIM: A meta-analysis of existing published trials was undertaken to evaluate the treatment effect of budesonide in collagenous colitis. METHODS: All pertinent literature sources were searched for published reports in English of budesonide use in collagenous colitis. MEDLINE and EMBASE databases were reviewed, as well as bibliographies from published articles and available abstracts from relevant meetings. Literature that met prespecified criteria was selected for the meta-analysis. RESULTS: Three trials were included in the meta-analysis. Budesonide significantly decreased stool frequency (budesonide vs. placebo OR: 20.1, 95% CI: 7.0-57.5, P < 0.0001). In general, budesonide treatment was well-tolerated. CONCLUSIONS: Budesonide is clinically effective short-term in collagenous colitis, and seems to be relatively well-tolerated. Clinicians can consider this drug as a reasonable option for patients with this disorder.

Anti-Inflammatory Agents↗
PubMed2005

Review article: drug-induced microscopic colitis - proposal for a scoring system and review of the literature.

The pathophysiology of microscopic colitis is unknown, although it is thought to be because of an abnormal immune reaction to luminal antigens in predisposed hosts. Specific antigens have not been proved, although various infectious triggers and drugs have been proposed. The responsibility of several drugs has been questioned, some with strong clinical and/or histological evidence suggesting causality. The issue of drug-induced microscopic colitis is important because of the burden of this disease. Thus, any case that can be cured by withdrawal of a drug must be identified. In this report, we propose a scoring system for drug-induced microscopic colitis, adapting existing criteria of drug causality, and review the literature using this framework. Based on this review, several drugs are identified with intermediate or high likelihood of inducing microscopic colitis. Finally, we suggest how to treat individual patients suspected of having drug-induced colitis according to the level of evidence for that particular drug.

Colitis, Microscopic↗
PubMed2006

Low-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treatment of active ulcerative colitis: a randomized, controlled, comparative study.

BACKGROUND: Heparin could be beneficial to the treatment of active ulcerative colitis because of its anticoagulant, anti-inflammatory and immunomodulatory properties. AIM: To evaluate the tolerability, safety and efficacy of low-molecular-weight heparin as adjuvant therapy in patients with active ulcerative colitis. METHODS: Thirty-four adult patients with active ulcerative colitis were consecutively included in a prospective, randomized, comparative study, and were treated for 12 weeks. Eighteen patients in the 'standard therapy' group were treated with aminosalicylates and weekly tapered corticosteroids. Sixteen patients in the 'heparin therapy' group were treated with standard therapy plus enoxaparin 100 Anti-Xa IU/kg/day subcutaneously. RESULTS: Seventeen patients in the 'standard therapy' group and 15 patients in the 'heparin therapy' group completed the study. Tolerability and compliance to therapy were excellent and no withdrawals were noted because of complications. There was a significant improvement in the disease severity in both groups (P<0.001), without any difference between them (P=not significant). Both treatment groups showed similar proportions of disease improvement (65% and 73%, respectively; P=not significant). There were no significant differences in inflammation (fibrinogen, ESR, CRP) and coagulation (thrombin-antithrombin complex, F1+2, D-dimers) parameters during and at the end of the study between treatment groups. CONCLUSION: Adjuvant administration of low-molecular heparin in patients with active ulcerative colitis is safe and well tolerated, but no additive benefit over standard therapy for ulcerative colitis was noted.

Adjuvants, Pharmaceutic↗
PubMed2006

Review article: induction therapy for patients with active ulcerative colitis.

5-aminosalicylic acid (mesalazine) is considered first-line therapy for active mild-moderate, left-sided or extensive ulcerative colitis. With modern delayed-release formulations, conventional doses are very well tolerated, and there is accumulating evidence that increasing the dose, to >4 g/day, leads to higher response rates and earlier symptom relief in patients with ulcerative colitis. There is evidence that combining oral and rectal (enema) formulations of 5-aminosalicylic acid leads to faster and higher remission rates. Despite the fact that clinical trials in ulcerative colitis have often used different endpoints, making it difficult to make objective comparisons, the evidence now strongly suggests that it is appropriate to start patients with mild or moderately active ulcerative colitis on doses of 5-aminosalicylic acid of at least 4 g/day. For those with extensive disease, adding rectal 5-aminosalicylic acid improves remission rates; the same seems likely to be true for limited disease, but robust evidence is lacking. Rectal 5-aminosalicylic acid may in fact be sufficient on its own for patients with active proctitis. Patients with mild-moderate ulcerative colitis who do not improve within 2 weeks of high-dose 5-aminosalicylic acid should have treatment augmented by oral steroids.

Administration, Oral↗
PubMed2004

Blocking lymphotoxin-beta receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte margination in chronic DSS-induced colitis.

The lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LTbetaR activation contributes to the pathology of chronic inflammation we used a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LTbetaR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LTbeta which constitutes part of the LTalpha(1)beta(2) ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LTbetaR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1beta, and IL-6. Moreover, LTbetaR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTbetaR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LTbetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis.

Animals↗
PubMed2005

Increased lymphocyte trafficking to colonic microvessels is dependent on MAdCAM-1 and C-C chemokine mLARC/CCL20 in DSS-induced mice colitis.

Although enhanced lymphocyte trafficking is associated with colitis formation, little information about its regulation is available. The aim of this study was to examine how the murine liver and activation-regulated chemokine (mLARC/CCL20) contributes to lymphocyte recruitment in concert with vascular adhesion molecules in murine chronic experimental colitis. T and B lymphocytes isolated from the spleen were fluorescence-labelled and administered to recipient mice. Lymphocyte adhesion to microvessels of the colonic mucosa and submucosa was observed with an intravital microscope. To induce colitis, the mice received two cycles of treatment with 2% dextran sodium sulphate (DSS). In some of the experiments antibodies against the adhesion molecules or anti-mLARC/CCL20 were administered, or CC chemokine receptor 6 (CCR6) of the lymphocytes was desensitized with excess amounts of mLARC/CCL20. Significant increases in T and B cell adhesion to the microvessels of the DSS-treated mucosa and submucosa were observed. In chronic colitis, the accumulation of lymphocytes was significantly inhibited by anti-mucosal addressin cell adhesion molecule (MAdCAM)-1 mAb, but not by anti-vascular cell adhesion molecule-1. In DSS-treated colonic tissue, the expression of mLARC/CCL20 was significantly increased, the blocking of mLARC/CCL20 by monoclonal antibody or the desensitization of CCR6 with mLARC/CCL20 significantly attenuated the DSS-induced T and B cell accumulation. However, the combination of blocking CCR6 with MAdCAM-1 did not further inhibit these accumulations. These results suggest that in chronic DSS-induced colitis, both MAdCAM-1 and mLARC/CCL20 may play important roles in T and B lymphocyte adhesion in the inflamed colon under flow conditions.

Animals↗
PubMed2005

Transgenic over-expression of macrophage migration inhibitory factor renders mice markedly more susceptible to experimental colitis.

Enhanced production of macrophage migration inhibitory factor (MIF) is recognized in patients with inflammatory bowel disease (IBD) and mice with experimental colitis; however, the precise molecular function of MIF in colitis is not fully understood. To further investigate this matter, we examined the pathological features of MIF transgenic mice with dextran sulphate sodium (DSS)-induced colitis. We generated transgenic mice carrying a murine MIF cDNA driven by a cytomegalovirus enhancer and a beta-actin/beta-globin promoter. Mice were orally administered 1-4% DSS in drinking water for 7 days. Clinical disease activity, survival and histological features were evaluated. The level of myeloperoxidase (MPO) activity in the colon tissue was measured to assess neutrophil infiltration. The level of corticosterone in the serum was measured by enzyme linked-immunosorbent assay (ELISA). MIF mRNA and protein were markedly up-regulated in the colon and serum obtained from MIF transgenic mice. The severity of the colitis induced by 1% DSS treatment was markedly higher in MIF transgenic mice than in wild-type mice. We also found that MPO activity was significantly higher in MIF transgenic mice than wild-type mice in response to DSS stimulation. Interestingly, the corticosterone level remained unchanged in MIF transgenic mice. MIF enhances DSS-induced colitis, in part via neutrophil accumulation and inhibition of glucocorticoid bioactivity.

Animals↗
PubMed2005

Analysis of intestinal haem-oxygenase-1 (HO-1) in clinical and experimental colitis.

Haem-oxygenase-1 (HO-1) has been shown to exert anti-inflammatory, anti-apoptotic and anti-proliferative effects. We investigated HO-1 expression in patients with inflammatory bowel disease (IBD) and could demonstrate a scattered expression of HO-1 in the intestinal epithelium of severely inflamed colonic mucosa of patients with IBD compared to control specimens such as diverticulitis, suggesting dysregulated expression in IBD. To further analyse potential mechanisms of HO-1 induction in the intestine we employed an in vitro epithelial cell apoptosis model and an experimental colitis model. In vitro induction of HO-1 by the HO-1 inducer cobalt protoporphyrin (CoPP) resulted in a dose-dependent down-regulation of caspase-3 activation in HT-29 cells, indicating an anti-apoptotic function of HO-1 in the intestine. In vivo, preventive HO-1 induction by CoPP in acute dextran sodium sulphate (DSS)-induced colitis led to a significant down-regulation of colonic inflammation (P < 0.01) with a concomitant reduction in interferon (IFN)-gamma - but unaffected interleukin (IL)-10-secretion by isolated mesenteric lymph nodes (P < 0.01). Additionally, TUNEL staining of colonic sections demonstrated fewer apoptotic epithelial cells in the colon of CoPP treated animals. No beneficial effects were observed if HO-1 was induced by CoPP after the onset of acute colitis or in chronic DSS-induced colitis. In conclusion, the data suggest a protective role of HO-1 if it is induced before the onset of inflammation. However, as shown by the lack of effects in established acute or in chronic colitis, the induction of HO-1 may not be a promising approach for the treatment of IBD.

Acute Disease↗
PubMed2005

Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice.

Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ((-/-)) mice. TLR4(-/-) mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-alpha in colon tissues was increased in WT mice but unchanged in TLR4(-/-) mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4(-/-) and WT mice. The expression of MIF was up-regulated in the colons of TLR4(-/-) mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4(-/-) mice. The current results obtained from TLR4(-/-) mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.

Acute Disease↗
PubMed2006

Involvement of 4-1BB (CD137)-4-1BBligand interaction in the modulation of CD4 T cell-mediated inflammatory colitis.

4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB-4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB-4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function.

4-1BB Ligand↗