Lithium And Graft Vs. Host Disease

At left, graft vs. host disease. By Reddy, P. and Ferrara, J.L.M., Mouse models of graft-versus-host disease (February 28, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.36.1, http://www.stembook.org/node/548 . - [1] DirectStemBook Figure 1 Three phases of GVHD immuno-biologyReddy, P. and Ferrara, J.L.M., Mouse models of graft-versus-host disease (February 28, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.36.1, http://www.stembook.org/node/548 ., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=25463572

Lithium may help alleviate intestinal graft-vs-host disease through the activation of Wnt signaling. This is another example of how basic science research (e.g., ell signaling) can eventually be used to help patients.  Abstract:

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.