TY - JOUR
T1 - Macrophage inflammatory protein-2 (MIP-2)/CXCR2 blockade attenuates acute graft-versus-host disease while preserving graft-versus-leukemia activity
AU - Cho, Kyung Ah
AU - Woo, So Youn
AU - Park, Yoon Shin
AU - Park, Min Hwa
AU - Ryu, Kyung Ha
N1 - Funding Information:
This work was supported by the Korea Food and Drug Administration in 2011 [grant number 11172KFDA367 ]. There are no financial conflicts of interest.
PY - 2012/10/5
Y1 - 2012/10/5
N2 - 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.
AB - 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.
KW - Bone marrow transplantation
KW - CXCR2
KW - Graft-versus-host disease
KW - Graft-versus-leukemia
KW - MIP-2
UR - http://www.scopus.com/inward/record.url?scp=84867220572&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2012.08.126
DO - 10.1016/j.bbrc.2012.08.126
M3 - Article
C2 - 22982307
AN - SCOPUS:84867220572
SN - 0006-291X
VL - 426
SP - 558
EP - 564
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -