IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects

Abstract

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 plays 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.

IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression

“…As an anti-inflammatory and immune inhibitory cytokine, IL-35 has been demonstrated to suppress T cell proliferation [1], convert naive T cells into IL-35-producing iTr35 [8], and play important roles in inflammatory diseases [9–10], infectious diseases [5, 11–12], autoimmune diseases [13–16], and allograft rejection [17–18]. …”

Islet antigen-pulsed dendritic cells expressing ectopic IL-35Ig protect nonobese diabetic mice from autoimmune diabetes

“…However, in another study in the same CIA model, a regulatory T cell subset characterized by CD4 and CD39 but not Foxp3 expression was demonstrated being capable of conferring protection upon treatment with exogenous IL-35 [12]. In a model of acute graft-versus-host disease, IL-35 overexpression in target organs mitigated the disease via induction of Foxp3 + Treg cells [47]. We therefore investigated whether IL-35, ectopically expressed by DCs, could also increase Treg cell populations in the NOD diabetes model.…”

Elevated IL-35 in bone marrow of the patients with acute myeloid leukemia

“…Liu et al have reported that IL-35 has an important role in reducing acute graft-versus-host disease (a-GVHD) through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as therapeutic strategy for a-GVHD [19]. Zhang et al have reported that IL-35 may affect the development of a-GVHD by inhibiting platelet activation and aggregation, suggesting that IL-35 represents a potentially effective therapeutic agent against a-GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) [20].…”