The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease - a phase 1 trial with three doses.

BACKGROUND: Mesenchymal stromal cells ability to reset immune functionalities may be useful in Crohn's disease. AIM: To perform a first-in-human phase 1 safety clinical trial of metabolically fit autologous bone marrow-derived mesenchymal stromal cells in 12 subjects with Crohn's disease utilising three doses. METHODS: Autologous mesenchymal stromal cells were derived from marrow aspirate and propagated for 2-3 weeks with fibrinogen depleted human platelet lysate and subsequently administered to subjects without interval cryobanking. Twelve subjects received a single mesenchymal stromal cell intravenous infusion of 2, 5 or 10 million cells/kg BW(n = 4/group). Infused mesenchymal stromal cells were analysed for cell surface marker expression, IDO(indoleamine 2,3-dioxygenase) upregulation by IFNγ stimulation, and inhibition of third party peripheral blood mononuclear cell proliferation in vitro. The primary end point measured was safety and tolerability; clinical response was assessed as a secondary endpoint. RESULTS: All patients tolerated the mesenchymal stromal cell infusion well and no dose limiting toxicity was seen. Seven patients had serious adverse events of which five were hospitalisations for Crohn's disease flare. Two of these serious adverse events were possibly related to the mesenchymal stromal cells infusion. Five subjects showed clinical response 2 weeks after the infusion. Mesenchymal stromal cell phenotype, cytokine responsiveness, and peripheral blood mononuclear cell proliferation blockade were not different among the patients. CONCLUSION: Single infusion of fresh autologous bone marrow mesenchymal stromal cells propagated ex vivo using human platelet lysate-supplemented media was safe and feasible at intravenous doses of up to 10 million cells/kg BW in patients with Crohn's disease.

Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease.

BACKGROUND AND AIMS: Crohn's disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn's disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn's disease. METHODS: Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn's disease, children with long-standing Crohn's disease, infectious colitis, and children without gut inflammation. RESULTS: As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn's disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-gamma production and IL12Rbeta2 chain expression. Th1 polarisation was not induced in clones from late Crohn's disease. Mucosal levels of IL12p40 and IL12Rbeta2 messenger RNA were significantly higher in children with early than late Crohn's disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn's disease. CONCLUSIONS: At the onset of Crohn's disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn's disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.

Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn's disease patients with prior anaphylactic reaction.

Infusion of the antitumor necrosis factor-alpha chimeric monoclonal antibody infliximab is highly effective in the treatment of refractory and fistulizing Crohn's disease (CD), but can be associated with the development of severe allergic reactions during retreatment, precluding further use of the medication. We present two CD patients (one adult and one child) with a history of anaphylactic/anaphylactoid reactions to retreatment with infliximab who subsequently underwent successful desensitization and therapeutic infusion using parenteral dose escalation in an intensive care unit setting.

Percutaneous colonoscopic cecostomy for management of chronic constipation in children.

BACKGROUND: Chronic constipation and encopresis are common problems in children with spina bifida and anorectal anomalies. Commonly used therapies include complicated bowel regimens and antegrade continence enemas delivered via surgically placed appendicostomies and radiologically placed cecostomies. METHODS: A technique is described for percutaneous placement of cecostomies for the delivery of continence enemas or venting. RESULTS: Percutaneous cecostomies were placed in 12 patients. Improvement in bowel management occurred in all patients. CONCLUSIONS: Percutaneous endoscopic cecostomy is a safe and effective method for the treatment of intractable constipation.

Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease.

OBJECTIVES: Tumor necrosis factor-alpha plays a central role in chronic intestinal inflammation of Crohn's disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn's disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn's disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn's disease. METHODS: Fifteen consecutive children (mean age 12.8 +/- 3.2 yr) with medically refractory Crohn's disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response. RESULTS: In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients. CONCLUSIONS: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn's disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn's disease.

Intrinsic hyperreactivity of mucosal T cells to interleukin-2 in pediatric Crohn's disease.

OBJECTIVES: To cells play a crucial role in many chronic inflammatory diseases. Mucosal T cells are particularly important in the pathogenesis of Crohn's disease (CD). We investigated the response of T cells in CD and other intestinal inflammatory conditions to interleukin-2 (IL-2), a cytokine essential for T-cell activation, growth, and function. STUDY DESIGN: T-cell reactivity was assessed by measuring growth induced by IL-2 in mucosal endoscopic biopsy specimens obtained from children with CD, ulcerative colitis, indeterminate colitis, and chronic nonspecific colitis and from children without gastrointestinal inflammation. RESULTS: CD mucosal T cells grew remarkably and significantly more than T cells from normal, ulcerative colitis, and chronic nonspecific colitis mucosa. T cells from indeterminate colitis mucosa grew similarly to those of CD mucosa. The enhanced growth response in CD was independent of disease location, presence or absence of intestinal inflammation, treatment, disease duration, or clinical activity. CONCLUSION: Mucosal T cells from children with CD exhibit an intrinsic hyperreactivity to IL-2. This may represent a primary pathogenic abnormality in this condition.

Liver biopsy findings in patients with juvenile rheumatoid arthritis receiving long-term, weekly methotrexate therapy.

We performed percutaneous liver biopsy in nine children who had received a weekly dose of methotrexate, 10 mg/m2 per week, for at least 3 years to address the concern about subclinical liver toxicity from single, weekly, low-dose methotrexate therapy for juvenile rheumatoid arthritis. No patient had clinical or biochemical evidence of liver injury. All biopsy results were interpreted as normal. These results suggest that the recommendations of the American College of Rheumatology for adults receiving single weekly methotrexate therapy for rheumatoid arthritis can be extended to children.