Acute epithelial injury in the rat small intestine in vivo is associated with expanded expression of transforming growth factor alpha and beta.

BACKGROUND--Previous studies have shown the importance of transforming growth factors alpha and beta (TGF alpha and TGF beta) in modulating epithelial cell restitution after injury in vitro. AIM--To investigate the role of the growth factors TGF alpha and TGF beta after acute epithelial injury in vivo. METHODS--An in vivo model of phytohaemagglutinin (PHA) induced acute epithelial injury in rat small intestine was used. Epithelial cell turnover was assessed by autoradiography and liquid scintillation counting of thymidine uptake. Expression of TGF alpha and TGF beta was assessed by immunohistochemistry. RESULTS--An expansion of the proliferative compartment and increased turnover of intestinal epithelial cells was seen in rats with PHA induced intestinal epithelial injury. Expression of TGF alpha and TGF beta peptides was shown in both the epithelial cell and lamina propria compartment. Different patterns of TGF alpha and TGF beta expression were seen, however, within the epithelium of rats with acute intestinal injury compared with untreated controls, while the expression of these peptides within the lamina propria was not changed. CONCLUSIONS--These findings suggest that acute intestinal epithelial cell injury in vivo is associated with compensatory changes in expression of TGF alpha and TGF beta in the epithelial cell compartment, while the lamina propria does not seem to be significantly affected

Prospective Randomized Open-label Multicenter Phase I/II Dose Escalation Trial of Visilizumab (HuM291) in Severe Steroid-refractory Ulcerative Colitis

Background: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). Methods: In all, 104 patients were treated. In Stage 1, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 mu g/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 mu g/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. Results: The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 70%, 50%, and 61%. respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 3.5%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. Conclusions: Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 mu g/kg/day were similar to those observed with higher doses (NCT00267306 at www.clinicaltrials.gov).Cellular mechanisms in basic and clinical gastroenterology and hepatolog