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

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 α4β7 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 α4β7‐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.