IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (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.
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We thank Karen Forbes and Creg Workman for generating and purifying the anti-Ebi3 mAb. 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). DAAV was supported by the National Institutes of Health (R01 AI091977), NCI Comprehensive Cancer Center Support CORE grant (CA21765) and ALSAC.
DAAV has submitted patents around IL-35 that are pending and is entitled to a share in net income generated from licensing of these patent rights for commercial development. The remaining authors declare no conflict of interest.
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