Regulatory Role of Host IL-17 Via Control of Host Macrophage Activation Contributes to Less Acute Gvhd

Abstract

AbstractAbstract 4669IL-17 has emerged as a key pro-inflammatory cytokine, however, recent studies demonstrated that IL-17 has also anti-inflammatory effects. In addition, a wide variety of IL-17 producing cells are identified not only in T-cells but also in subpopulation of monocytes and macrophages, mast cells, Paneth cell in the gut so on. Therefore, IL-17 mediated immune responses are becoming much more complicated. In hematopoietic stem cell transplantation, we have reported that host-derived IL-17 has a protective effect against acute graft-versus-host disease (GVHD) using rodent models, in contrast, donor-BM-derived IL-17 exacerbates chronic GVHD. In acute GVHD model, lethally irradiated IL-17 knockout (KO) recipient mice receiving allogeneic BM with low dose splenocytes developed more severe acute gut GVHD compared to wild type (WT) host mice and finally half of them died (p<0.05). Much higher number of infiltrated monocyte/macrophage cluster was observed in spleen and gut in IL-17 KO host mice. Furthermore, residual host-typed peritoneal macrophages in IL-17 KO host mice were highly activated with the expression of TNF-α, while activation of donor-typed macrophages was much less with the production of anti-inflammatory cytokine IL-10. It suggested that these activated and increased macrophages might deeply involve in the pathogenesis of lethal GVHD. To test this, IL-17 KO recipient mice were given lipoCL2MDP intraperitoneally on day -7 before BMT to deplete host macrophages. As shown in the figure below, the macrophages depleted IL-17 KO host mice given splenocytes to induce lethal GVHD showed a significant survival benefit compared with IL-17 KO mice without depletion of macrophages. In conclusion, host IL-17 has a protective effect against acute GVHD with suppression of the activated macrophages. This is the first report that IL-17 has the immuno-regulatory role via control of activated host macrophages in acute GVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.