Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood 2010 Jun 24;115(25):5249-58
Date
04/13/2010Pubmed ID
20382845Pubmed Central ID
PMC2892952DOI
10.1182/blood-2009-11-255422Scopus ID
2-s2.0-77954687870 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.
Author List
Das R, Komorowski R, Hessner MJ, Subramanian H, Huettner CS, Cua D, Drobyski WRAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinMartin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acute DiseaseAnimals
Chronic Disease
Colon
Colonic Diseases
Disease Models, Animal
Graft vs Host Disease
Graft vs Leukemia Effect
Humans
Interleukin-23 Subunit p19
Leukemia
Mice
Mice, Inbred BALB C
Mice, Knockout
Signal Transduction
Stem Cell Transplantation
Transplantation, Homologous