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Published online before print October 19, 2006

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(Journal of Leukocyte Biology. 2007;81:176-185.)
© 2007 by Society for Leukocyte Biology

Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects

Satoshi Ueha^*, Masako Murai^*, Hiroyuki Yoneyama^*, Masahiro Kitabatake^*, Toshio Imai, Takeshi Shimaoka^*,, Shin Yonehara, Sho Ishikawa^* and Kouji Matsushima^*,1

^* Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan;
Kan Research Institute, Kyoto, Japan; and
Graduate School of Biostudies and Institute for Virus Research, Kyoto University, Kyoto, Japan

¹Correspondence: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: koujim{at}m.u-tokyo.ac.jp

ABSTRACT

Coincidence of the beneficial graft-vs.-tumor (GVT) effects and the detrimental graft-vs.-host disease (GVHD) remains the major obstacle against the widespread use of allogeneic bone marrow transplantation (BMT) as tumor immunotherapy. We here demonstrate that intervention of MAdCAM-1 (mucosal vascular addressin cell adhesion molecule-1) or fractalkine/CX₃CL1 after the expansion of allo-reactive donor CD8 T cells selectively inhibits the recruitment of effector donor CD8 T cells to the intestine and alleviates the graft-vs.-host reaction (GVHR) associated intestinal injury without impairing GVT effects. In a nonirradiated acute GVHD model, donor CD8 T cells up-regulate the expression of intestinal homing receptor 4ß7 and chemokine receptors CXCR6 and CX₃CR1, as they differentiate into effector cells and subsequently infiltrate into the intestine. Administration of anti-MAdCAM-1 antibody or anti-fractalkine antibody, even after the expansion of alloreactive donor CD8 T cells, selectively reduced the intestine-infiltrating donor CD8 T cells and the intestinal crypt cell apoptosis without affecting the induction of donor derived anti-host CTL or the infiltration of donor CD8 T cells in the hepatic tumor. Moreover, in a clinically relevant GVHD model with myeloablative conditioning, these antibodies significantly improved the survival and loss of weight without impairing the beneficial GVT effects. Thus, interruption of 4ß7-MAdCAM-1 or CX₃CR1-fractalkine interactions in the late phase of GVHD would be a novel therapeutic approach for the separation of GVT effects from GVHR-associated intestinal injury.

Key Words: chemokines • cell trafficking • mucosa • adhesion molecule • tumor

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