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* Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China;
Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
Department of Immunology, Soochow University, Suzhou, China;
Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
¶ Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
|| Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and
# Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8+ T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8+ T cells generate two subsets of potent inducers of GVHD: CXCR3+CD8+ and CXCR3–CD8+ T cells. Compared with CXCR3+CD8+ T cells, CXCR3–CD8+ T cells produce less granzyme B, Fas ligand, IFN-
, and TNF-
. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3+CD8+ and CXCR3–CD8+ T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3+CD8+ T cell-mediated GVHD, but not the disease induced by CXCR3–CD8+ T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8+ T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3+CD8+ or CXCR3–CD8+ T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Natural Science Foundation of China (NSF30670911 and NSF 30873045), the programs of the Science and Technology Commission of Shanghai Municipality (03JC14085, 06DZ19020, and 074319102), and the Shanghai Leading Academic Discipline Project (T0206).
2 Drs. Yanyun Zhang and Dr. Yi Zhang contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Yanyun Zhang, Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China. E-mail address: yyzhang{at}sibs.ac.cn or Dr. Yi Zhang, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. E-mail address: yizha{at}med.umich.edu
4 Abbreviations used in this paper: GVHD, graft-versus-host disease; CDC, complement-dependent cytotoxicity; CT, cycle threshold; DC, dendritic cell; FasL, Fas ligand; GVH, graft-vs-host; GVL, graft-vs-leukemia; HSCT, hematopoietic stem cell transplantation; miHA, minor histocompatibility Ag; PI, propidium iodide; TCD BM, T cell-depleted bone marrow cells; Wt, wild type.
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