Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease

Contains fulltext : 177233.pdf (publisher's version ) (Open Access)Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury. TRIAL REGISTRATION: ClinicalTrials.gov NCT00408681

Selective protection by hsp 70 against cytotoxic drug-, but not Fas-induced T-cell apoptosis

The phenomenon of heat-shock (HS) protection to many cytotoxic insults has previously been described; however, the specific molecular mechanism underlying this HS-mediated protection remains undefined. To gain insight into this protective mechanism, heat-shocked Jurkat T cells were treated with a range of cytotoxic agents. Those against which HS conferred protection (camptothecin and actinomycin D) were compared with agents against which HS showed no protective effect (anti-Fas monoclonal antibody (mAb)). Reactive oxygen species (ROS) production was found to be an event common to apoptosis induced by camptothecin and actinomycin D, whereas Fas-mediated apoptosis was shown to occur via a ROS-independent mechanism. The selective protection observed against these agents was found to be mimicked by pretreatment with antioxidant compounds. Furthermore, this antioxidant protection appears to be occurring downstream of ROS production. Experiments were extended using heat-shock protein (hsp) 70 gene-transfected Jurkat T cells to confirm that the protective effects observed were caused by hsp 70 synthesis rather than any other cellular response to HS. Bcl-2 expression levels were also examined to determine whether any correlation existed between Bcl-2- and hsp 70-mediated protection