Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects.
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 alpha4beta7 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 alpha4beta7-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.
Ueha
Satoshi
S
Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Murai
Masako
M
Yoneyama
Hiroyuki
H
Kitabatake
Masahiro
M
Imai
Toshio
T
Shimaoka
Takeshi
T
Yonehara
Shin
S
Ishikawa
Sho
S
Matsushima
Kouji
K
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000276:immunology / Q000502:physiology*; D006086:Graft vs Host Disease / Q000473:pathology*; D006087:Graft vs Host Reaction / Q000276:immunology*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008565:Membrane Proteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins
D000906:Antibodies; D015815:Cell Adhesion Molecules; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; C489082:Madcam1 protein, mouse; D008565:Membrane Proteins; D009088:Mucoproteins