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 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.

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

“…39,65 CXCR6 has been shown to be expressed on liverinfiltrating CD8 þ T cells after allo-BMT and to be functionally involved in the early recruitment of these cells to the liver, but not to the gut. 66,67 Consistent with these findings, in this study, hepatic expression of both CXCR6 and its ligand, CXCL16, was strongly elevated from week 1 to week 3, supporting the concept that the migration of CXCR6 þ T cells to the liver in response to increased ligand expression is operative in aGVHD of the liver. Intestinal CXCL16 expression was not altered at 1 week after allo-BMT and then continuously increased from week 2 to week 6.…”

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

“…34,35 Reduction in plasma concentrations of chemotactic factors indicates a reduction in immune cell recruitment to sites of active cGVHD. [36][37][38][39] Furthermore, changes in levels of tissue factors associated with fibrosis suggest a decreased propensity for tissue fibrosis and restoration of normal organ function. 40,41 These findings, together with the demonstration of clinical response across multiple organs, support the hypothesis that ibrutinib is affecting cGVHD at a pathogenic level and not just treating symptoms of cGVHD.…”

Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice

“…32 In brief, cryosections were fixed in ice-cold acetone and preincubated in Block Ace (Dainippon Pharmaceutical, Tokyo, Japan). Subsequently, samples were incubated with primary antibodies or appropriate control antibodies, followed by appropriate Alexa Fluor-labeled secondary reagents (Invitrogen Japan K.K., Tokyo, Japan).…”