Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis.

BACKGROUND/AIM: Active ulcerative colitis (UC) is often associated with increased peripheral granulocytes and monocytes/macrophages which show activation behavior and prolonged survival time. Further, mucosal granulocyte level parallels intestinal inflammation and can predict UC relapse. Accordingly, our aim was to see if adsorptive granulocyte/monocyte apheresis (GMA) can promote remission and spare steroid in patients with steroid-dependent (SD) UC. METHODS: 69 SD patients, at the time of relapse, were randomly assigned to groups I (n = 46) and II (n = 23). The mean dose of prednisolone (PSL) was 12 mg/day/patient, CAI (clinical activity index) 9.2 in both groups. Group I patients were given up to 11 GMA sessions over 10 weeks with Adacolumn; in group II, the mean dose of PSL was increased to 30 mg/day/patient. RESULTS: At week 12, 83% of group I and 65% of group II patients were in remission, CAI in group I was 1.7 (p < 0.001) and in group II, 2.5 (p < 0.001). Further, during the 12 weeks of treatment, the cumulative amount of PSL received per patient was 1,157 mg in group I and 1,938 mg in group II (p = 0.001). CONCLUSIONS: GMA appeared to be an effective adjunct to standard drug therapy of moderately severe UC by promoting remission and sparing steroids.

Correlation of serum soluble TNF-alpha receptors I and II levels with disease activity in patients with ulcerative colitis.

OBJECTIVES: TNF-alpha has a major role in inflammatory bowel disease via two receptors, p55 (RI) and p75 (RII) expressed on many cell types, in particular neutrophils and monocytes (GM). Upon activation of these leukocytes, RI and RII are shed into the medium and can neutralize TNF. Accordingly, soluble RI and RII (s-RI/RII) are believed to have potent antiinflammatory actions. Further, in active UC, GM are elevated with activation behavior and recently adsorptive GM apheresis (GMA) in patients with severe UC was associated with a dramatic efficacy. In this study, we investigated the effects of GMA on serum s-RI/RII. METHODS: Thirty-one patients with UC, clinical activity index (CAI) 11.1 were treated with GMA by using the Adacolumn. In the column, leukocytes which bear the FcgammaR and complement receptors adhere to the column apheresis carriers (neutrophils, monocytes, and a small fraction of lymphocytes). One GMA session was 60 min at 30 mL/min and each patient could receive up to 11 sessions over 8 wk. Serum s-RI/II were measured in the blood at the column inflow (peripheral blood, time 0 and 60 min) and outflow at 60 min. RESULTS: Serum s-RI/RII showed strong correlation with CAI, r = 0.849 (p < 0.001) and r = 0.867 (p < 0.001), respectively and were greater than when patients were in remission or the levels in controls (p < 0.001). s-RI/RII at the column outflow were higher compared with inflow (p < 0.05) suggesting that RI/RII were shed from leukocytes which adhere to the carriers. Similarly s-RI/RII were significantly increased in the peripheral blood at the end of the 60 min GMA session compared with time 0. After 11 GMA sessions, CAI fell to remission level in 26 of 31 patients accompanied by falls of s-RI/RII. CONCLUSIONS: The sources of s-RI/RII are believed to be activated monocytes and neutrophils with further release when these leukocytes adhere to the column carriers. s-RI/RII released during GMA should contribute to the clinical efficacy of this procedure.

Evidence for the critical role of interleukin-12 but not interferon-gamma in the pathogenesis of experimental colitis in mice.

BACKGROUND AND AIMS: The imbalance between helper T (Th)1/Th2 cytokines has been observed in human inflammatory bowel disease and various animal models. Because interleukin (IL)-12 and interferon-gamma (IFN-gamma) productions are known to be a hallmark of Th1-dominant intestinal inflammation such as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we strictly addressed the roles of IFN-gamma and IL-12 in the development of colitis, employing knockout mice with IFN-gamma receptor (IFN-gammaR) or IL-12 p40 gene disruptions and mice administered with neutralizing monoclonal antibodies (mAbs) against IFN-gamma or IL-12. METHODS: To induce colitis, 2.5 mg of the hapten reagent TNBS in 50% ethanol was administered into the colon. Two milligrams of rat anti-mouse IFN-gamma mAb, rat anti-mouse IL-12 mAb, or control rat IgG were administered intraperitoneally into mice before TNBS administration. Change in the body weight of mice was evaluated and the degree of inflammation of the colon of these mice was investigated histologically. Immunohistochemical and immunofluorescence analyses were performed to detect CD4+ T cells, macrophages and IL-12 in TNBS-induced colitis lesions. The profile of Th1 and Th2 cytokine expressions in colonic tissues was examined by cytokine-specific semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Single rectal administration of TNBS developed significant colitis in IFN-R-/- mice and anti-IFN-gamma mAb-pretreated mice, as well as control wild-type mice. Conversely, administration of TNBS produced no signs of colitis in IL-12 p40-/- and anti-IL-12 mAb-pretreated mice. CONCLUSIONS: IL-12, but not IFN-gamma, plays a pivotal role in the pathogenesis of TNBS-induced colitis.

Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study.

BACKGROUND AND AIMS: Active ulcerative colitis (UC) is characterized by infiltration of activated granulocytes and monocytes/macrophages (GM) within the large bowel mucosa. GM are major sources of inflammatory cytokines, and in UC they are elevated with increased survival time. We investigated the possibility that reducing the level of these cells might promote remission of active UC. METHODS: Thirty-one patients with active corticosteroid refractory (refractory) UC, mean age of 42 years, duration of UC 6 years, clinical activity index (CAI) of 15, disease activity index (DAI) of 10, and 8 corticosteroid naive patients (naive), mean age of 36 years, duration of UC 2 years, CAI of 11, DAI of 8 were recruited. Each patient was treated with up to 11 cycles of granulocyte and monocyte adsorptive apheresis over 11 weeks by using a 335-mL capacity column filled with cellulose acetate beads that adsorb GM. RESULTS: At week 12, 81% of refractory (CAI, 3; P < 0.001 and DAI, 4; P < 0.001) and 88% of naive (CAI, 1; P = 0.012 and DAI, 3; P = 0.011) patients achieved remission. Early relapse was not a feature, and at 12 months, 26 of 33 patients had maintained their remission. The treatment was well tolerated, and no severe side effects were observed. CONCLUSIONS: The outcome of this study suggests that reduction of circulating granulocytes and monocytes results in alleviation of inflammation and promotes clinical remission in patients with severe active UC that has not responded to intensive corticosteroid treatment. These data suggest that formal controlled studies are warranted.

Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice.

BACKGROUND & AIMS: Curcumin is known to have a variety of pharmacologic effects, including antitumor, anti-inflammatory, and anti-infectious activities. The pleiotropic effects of curcumin are attributable at least in part to inhibition of transcriptional factor nuclear factor kappaB (NF-kappaB). However, the effect of curcumin on intestinal inflammation has hitherto not been evaluated. The aim of this study was to determine whether treatment with curcumin prevents and ameliorates colonic inflammation in a mouse model of inflammatory bowel disease. METHODS: Mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis were treated with 0.5%, 2.0%, or 5.0% curcumin in the diet, and changes in body weight together with histologic scores were evaluated. Colonic T-cell subsets were characterized, and NF-kappaB in colonic mucosa was detected by immunohistochemistry. NF-kappaB activity in the colonic mucosa was evaluated using electrophoretic mobility shift assay. Cytokine messenger RNA expression in colonic tissue was assessed by semiquantitative reverse-transcription polymerase chain reaction. RESULTS: Treatment of mice with curcumin prevented and improved both wasting and histopathologic signs of TNBS-induced colonic inflammation. Consistent with these findings, CD4(+) T-cell infiltration and NF-kappaB activation in colonic mucosa were suppressed in the curcumin-treated group. Suppression of proinflammatory cytokine messenger RNA expression in colonic mucosa was also observed. CONCLUSIONS: This study has shown for the first time that treatment with curcumin can prevent and improve murine experimental colitis. This finding suggests that curcumin could be a potential therapeutic agent for the treatment of patients with inflammatory bowel disease.