On November 3, 2014, researchers at Haiyan Liu’s group published an article entitled “IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects” in Leukemia.
IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acutegraft-versus-hostdisease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4+ effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4+Foxp3+ Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4+ T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD
Yuejun Liu and Yan Wu are the first authors of the paper. Contributing author are Ying Wang, Yifeng Cai, Bo Hu, Guangming Bao, Hongying Fang, Lixiang Zhao, Shoubao Ma, Qiao Cheng, Yuan Song, Yonghao Liu, Ziling Zhu, Huirong Chang, Xiao Yu, Aining Sun, Yi Zhang and Dario A. A. Vignali. Prof. Haiyan Liu and Prof Depei Wu are the corresponding authors of the paper. This work has been supported by the grants from National Natural Science Foundation of China (91029703, 81102271 and 81273268), the project funding from Suzhou city (SS201032, SZS201109), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Province’s Key Medical Center (ZX201102), 2012 Jiangsu Provincial Special Program of Medical Science (BL2012005), National clinical key subject construction project, National Public Health Grand Research Foundation (201202017), Jiangsu Provincial Innovative Research Team, Qing Lan project of Jiangsu Province, Program for Changjiang Scholars and Innovative Research Team in University (IRT1075). D.A.A.V. was supported by the National Institutes of Health (R01 AI091977), NCI Comprehensive Cancer Center Support CORE grant (CA21765), and ALSAC.