Prevention of Autoimmune Diabetes by Ectopic Pancreatic β-Cell Expression of Interleukin-35

Abstract

Interleukin (IL)-35 is a newly identified inhibitory cytokine used by T regulatory cells to control T cell–driven immune responses. However, the therapeutic potential of native, biologically active IL-35 has not been fully examined. Expression of the heterodimeric IL-35 cytokine was targeted to β-cells via the rat insulin promoter (RIP) II. Autoimmune diabetes, insulitis, and the infiltrating cellular populations were analyzed. Ectopic expression of IL-35 by pancreatic β-cells led to substantial, long-term protection against autoimmune diabetes, despite limited intraislet IL-35 secretion. Nonobese diabetic RIP-IL35 transgenic mice exhibited decreased islet infiltration with substantial reductions in the number of CD4+ and CD8+ T cells, and frequency of glucose-6-phosphatase catalytic subunit–related protein-specific CD8+ T cells. Although there were limited alterations in cytokine expression, the reduced T-cell numbers observed coincided with diminished T-cell proliferation and G1 arrest, hallmarks of IL-35 biological activity. These data present a proof of principle that IL-35 could be used as a potent inhibitor of autoimmune diabetes and implicate its potential therapeutic utility in the treatment of type 1 diabetes.

IL-12-and IL-23 in health and disease

“…Ebi3-deficient Tregs were incapable of controlling the expansion of effector T cells and were unable to reverse colitis compared with IL-35-competent Tregs [11]. Tissue specific expression of IL-35 using transgenic models was also shown to reduce auto-aggressive T cell-mediated tissue damage, highlighting a highly suppressive function of secreted IL-35 [12].…”

Epstein-Barr virus-induced gene 3-deficiency leads to impaired antitumor T-cell responses and accelerated tumor growth

“…15 has been shown to suppress T-cell proliferation, 3,4 Th17 and Th2 immune responses, and inhibit experimental arthritis, 3 airway inflammation 16 and diabetes mellitus in non-obese diabetic (NOD) mice. 17 …”

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

“…However, prototypical autoimmune rather than inflammatory diseases such as type 1 diabetes, caused by a T-cell mediated response that destroys insulin-producing pancreatic cells, may benefit more from the potentiation of suppressive cytokines, since prevention of autoimmune T cell reactivity and expansion of tolerogenic cell subsets would allow the early blockade of self-tissue destruction [8,[44][45][46]. Particularly interesting in this regard, Bettini and coworkers previously reported a protective suppressive effect of IL-35 in NOD mice following transgenic bicistronic expression of IL-35 chains in pancreatic b-cells [22], thus providing a proof-of-concept for protective effects of IL-35 in experimental autoimmune diabetes.…”

“…In addition, several studies have demonstrated IL-35 being expressed in different tumors [15,18,19], whereby it promotes angiogenesis and neoplastic growth by suppressing anti-tumor immunity [20]. Nevertheless, exogenous administration of rIL-35, or its ectopic expression (i.e., in cells normally nonexpressing the cytokine), was found to be protective in pathological conditions such as overwhelming inflammation combined with uncontrolled autoimmune responses, namely CIA [12], experimental autoimmune encephalomyelitis (EAE) [21], autoimmune diabetes [22], inflammatory bowel disease [15,23], atherosclerosis [24] and allergic airway inflammation [25].…”