Blockade of osteopontin reduces alloreactive CD8+ T cell-mediated graft-versus-host disease.
Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8(+) T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8(+) T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8(+) T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8(+) T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai, China.
Fang
F
Zhao
Yi
Y
Zhang
Hao
H
Wang
Min
M
Jin
Shan
S
He
Yufang
Y
Shi
Yajun
Y
Guo
Yanyun
Y
Zhang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007942:Leukemia, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D053495:Osteopontin