Suppression of Murine Allergic Airway Disease by IL-2:Anti-IL-2 Monoclonal Antibody-Induced Regulatory T Cells

Abstract

*Regulatory T cells (Treg) play a decisive role in many diseases including asthma and allergen-induced lung inflammation. However, little progress has been made developing new therapeutic strategies for pulmonary disorders. In the current study we demonstrate that cytokine:antibody complexes of IL-2 and anti-IL-2 mAb reduce the severity of allergen-induced inflammation in the lung by expanding Tregs in vivo. Unlike rIL-2 or anti-IL-2 mAb treatment alone, IL-2:anti-IL-2 complexes dampened airway inflammation and eosinophilia while suppressing IL-5 and eotaxin-1 production. Mucus production, airway hyperresponsiveness to methacholine, and parenchymal tissue inflammation were also dramatically reduced following IL-2:anti-IL-2 treatment. The suppression in allergic airway disease was associated with a marked expansion of Tregs (IL-10 ؉ CD4 ؉ CD25 ؉ and Foxp3 ؉ CD4 ؉ CD25 ؉ ) in the tissues, with a corresponding decrease in effector T cell responses. The ability of IL-2:anti-IL-2 complexes to suppress airway inflammation was dependent on Treg-derived IL-10, as IL-10 ؉/؉ , but not IL-10 ؊/؊ Tregs, were capable of mediating the suppression. Furthermore, a therapeutic protocol using a model of established airway allergy highlighted the ability of IL-2:anti-IL-2 complexes to expand Tregs and prevent successive airway inflammation and airway hyperresponsiveness. This study suggests that endogenous Treg therapy may be a useful tool to combat the rising incidence of allergic airway disease.

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

“…Notably, IL-2-mediated pulmonary edema was not an issue when Treg numbers were raised after a brief course of IL-2/mAb CD25 injections or with low doses of IL-2/mAb CD25 treatment. These latter approaches might be useful for the treatment of allergies, autoimmune disease, and allograft rejection (11,28,30).…”

Th2 Cytokines Augment IL-31/IL-31RA Interactions via STAT6-dependent IL-31RA Expression

“…Previously, we have demonstrated that SEA acts as a potent allergen and induces Th2-cytokine-driven allergic inflammation and airway hyper-responsiveness in a mouse model of allergic asthma (20,24). To identify the effect of Type II Th2 cytokine receptors on IL-31RA expression in vivo during allergic lung disease, we studied IL-31RA expression in WT and IL-13R␣2 Ϫ/Ϫ mice exposed to SEA.…”

“…6A, mice were sensitized and challenged twice with either SEA or PBS as a control. As described previously, SEA-induced allergic disease requires no adjuvant and is sufficient to induce inflammation and hyper-responsiveness in airways (20,24). PBS-or SEA-challenged lungs were collected at 24 h after the final challenge.…”

Interleukin-2: Biology, Design and Application

“…IL-2/JES6-1 complexes are also stimulatory for ILC2 that express trimeric IL-2Rs, which contributes to IL-5 production and eosinophilia [30,57]. IL-2/JES6-1 complexes have shown promising results in the prevention of pancreatic [56] and skin [58] allograft rejection as well as in the treatment of several autoimmune and inflammatory diseases in mice, including type 1 diabetes in nonobese diabetic mice [59], experimental autoimmune encephalomyelitis (a model of multiple sclerosis) [56], experimental myasthenia [60], collagen-induced arthritis [61], dextran sodium sulfate-induced acute colitis [13], and T cell-mediated allergic airway disease [62]. Interestingly, administration of IL-2/JES6-1 complexes also improved the pathology of some metabolic, cardiovascular, and degenerative disorders, such as murine obesity-induced inflammation and insulin resistance ('type 2 diabetes') [63], atherosclerosis in high-fat diet-fed apolipoprotein E-deficient animals [64], and the mdx mouse model of Duchenne muscular dystrophy [65], that feature inflammatory infiltrates and are thus amenable to suppression by CD25 + Foxp3 + Treg cells.…”