title: Macrophage inflammatory protein-2 (MIP-2)/CXCR2 blockade attenuates acute graft-versus-host disease while preserving graft-versus-leukemia activity.
abstract: Allogenic bone marrow transplantation (BMT), an important treatment for hematological malignancies, is often complicated by graft-versus-host disease (GVHD). Suppression of GVHD is associated with the unwanted diminishment of the graft-versus-leukemia (GVL) response. The aim of this study was to maintain the benefits of GVL during GVHD suppression through isolated blockade of T-cell migration factors. To this end, we developed a murine model of B-cell leukemia, which was treated with BMT to induce GVHD. Within this model, functional blockade of MIP-2/CXCR2 was analyzed by observing proteomic, histologic and clinical variables of GVHD manifestation. Luminex assay of collected tissue identified several cytokines [granulocyte colony-stimulating factor (G-CSF), keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2), and interleukin-23 (IL-23)] that were upregulated during GHVD, but reduced by neutralizing the MIP-2/CXCR2 axis. In addition, donor T-cell blockade of CXCR2 combined with recipient administration of anti-MIP-2 caused a significant decrease in GVHD while preserving the GVL response. We propose that blocking the MIP-2/CXCR2 axis represents a novel strategy to separate the toxicity of GVHD from the beneficial effects of GVL after allogenic BMT.
authors.affiliation: Department of Microbiology, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Cho
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Woo
authors.forename: Yoon Shin
authors.initials: YS
authors.lastname: Park
authors.forename: Min Hwa
authors.initials: MH
authors.lastname: Park
authors.forename: Kyung-Ha
authors.initials: KH
authors.lastname: Ryu
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054426:Chemokine CXCL2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D054426:Chemokine CXCL2; D023063:Receptors, Interleukin-8B