The role of macrophages in the mitigation by decitabine of acute allograft rejection.

INTRODUCTION: We have recently shown that the DNA hypomethylating agent decitabine (DAC) rescues lung allografts from acute rejection. This involves a mechanism that is dependent on host CD4+ FoxP3+ T cells for maximal benefit. DAC treatment also reduces host T-cell IFN-γ production. We therefore hypothesized that DAC may also reduce host macrophage activation. Our objective was to determine if an effect on macrophages contributes to the beneficial effects of DAC in transplantation. METHODS: In murine orthotopic lung transplant, hosts were treated on post-op day 3-8 with Clodronate (n = 5), DAC (n = 9), or DMSO (n = 11). RESULTS: Partial macrophage depletion (clodronate) improves allograft gross and histologic integrity. DAC-mediated allograft rescue was associated with reduced host macrophage recruitment into allograft airways, reduced activation of recruited macrophages, and regeneration of donor resident alveolar macrophages. DISCUSSION: These findings suggest that infiltrating host macrophages promote allograft rejection. They also suggest that donor alveolar health is indicative and/or promoting of allograft tolerance.