IL-17C Mitigates Murine Acute Graft-vs.-Host Disease by Promoting Intestinal Barrier Functions and Treg Differentiation.

Huanle Gong,Yonghao Liu,Ying Zhu,Hong Liu,Bo Hu,Yuan Song,Yang Xu,Chen Dong,Depei Wu,Shuangzhu Liu,Yuejun Liu,Lei Lei,Haiyan Liu,Shoubao Ma,Yan Wu,Yu Mei,Ziqi Jin

doi:10.3389/fimmu.2018.02724

Abstract

Acute graft-vs.-host disease (aGVHD) is one of the major complications and results in high mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-17C is involved in many inflammatory immune disorders. However, the role of IL-17C in aGVHD remains unknown. Here we demonstrated that IL-17C deficiency in the graft significantly promoted alloreactive T cell responses and induced aggravated aGVHD compared with wildtype donors in a fully MHC-mismatched allo-HSCT model. In contrast, IL-17C overexpression ameliorated aGVHD. IL-17C deficiency increased intestinal epithelial permeability and elevated inflammatory cytokine production, leading to an enhanced aGVHD progression. Tregs was reduced in recipients of IL-17C−/− graft, whilst restored after IL-17C overexpression. Decreased Treg differentiation was abrogated after neutralizing IFN-γ, but not IL-6. Moreover, depletion of Tregs diminished the protective effect of IL-17C. Of note, patients with low IL-17C expression displayed higher aGVHD incidence together with poor overall survival, thereby IL-17C could be an independent risk factor for aGVHD development. Our results are the first demonstrating the protective role of IL-17C in aGVHD by promoting intestinal barrier functions and Treg differentiation in a MHC fully mismatched murine aGVHD model. IL-17C may serve as a novel biomarker and potential therapeutic target for aGVHD.

Highlights

Allogeneic hematopoietic stem cell transplantation is a curative therapeutic strategy for treating malignant hematological diseases
To assess the possible role of IL-17C in the pathogenesis of acute graft-vs.-host disease (aGVHD), we first examined the expressions of IL-17C and IL17RE on day 3, 7, 12 post syngeneic and allogeneic HSCT by real-time PCR (Supplemental Figure 1)
In order to determine whether IL-17C produced by bone marrow (BM) cells or splenocytes is required for aGVHD protection, we performed the transplant with either IL-17C−/− BM or splenocytes together with the WT controls (Figure 1F)

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic strategy for treating malignant hematological diseases. Acute graft-vs.-host disease (aGVHD) is one of the major complications of allo-HSCT, limiting its clinical application, and prognosis [1]. Occurrence of aGVHD is predominantly induced by activation of donor-derived T cells and the production of proinflammatory cytokines, resulting in the damage of host organs such as liver, lung, gut, and skin [2]. Presence of inflammatory milieu is critical for the initiation of aGVHD. IL-17C Mitigates Acute Graft-Versus-Host Disease and amplification of alloreactive T cell responses [3, 4]. Proinflammatory cytokines including IL-1, IL-6, IFN-γ, and TNF-α contribute to the inflammatory settings and substantially promote the pathogenesis of aGVHD [5,6,7]. Developing effective therapies to mitigate inflammation is vital in prevention and treatment of aGVHD

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Results

Conclusion