Macrophage Inflammatory Protien-2/CXCR2 Blockade Attenuates Acute Graft-versus-Host Disease while Preserving Graft-versus-Leukemia Activity (126.16)

Abstract

Abstract Graft-versus-host disease (GVHD) is the principal complication after allogeneic bone marrow transplantation (BMT). Strategies that effectively separate the beneficial GVL effects from GVHD toxicity are necessary for enhanced survival after BMT. GVHD mice were induced by infusion of both donor BM cells and spleen cells into BU-CY conditioned recipient female BALB/c mice. Tumor-bearing GVHD mice were also made adding A20 cells. A total of 31 cytokines and chemokines were measured in the liver, intestine, and skin in GVHD mice by Luminex Multiplex assay. Four cytokines, G-CSF, KC, MIP-2, and IL-23, were commonly unregulated in target organs at the initial GVHD stage and were reduced by neutralizing MIP2/CXCR2 axis ligation. CXCR2 blockade on donor T cells and systemic administration of anti-MIP-2 neutralizing antibodies to BMT recipients caused a significant decrease in both systemic GVHD and target organ histopathology. GVL responses (BCL2 expression or B220+/CD19+ cells in BM and PB) after MIP-2/CXCR2 blockade were largely preserved and mortality was significantly delayed compared to control allogeneic BMT recipients. These data suggest that blocking the MIP-2/CXCR2 axis represents a novel strategy to separate the toxicity of GVHD from the beneficial GVL effects after allogeneic BMT.