Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma.

RATIONALE: Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. OBJECTIVES: We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. METHODS: Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. MEASUREMENTS AND MAIN RESULTS: The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo. CONCLUSIONS: IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

pH-specific sequestration of phosphoglucose isomerase/autocrine motility factor by fibronectin and heparan sulphate.

Phosphoglucose isomerase (PGI) is a glycolytic enzyme that moonlights as a cytokine under the aliases autocrine motility factor (AMF), neuroleukin and maturation factor. The cytokine function of PGI/AMF targets multiple cell types however mechanisms that regulate and sequester this ubiquitous, circulating cytokine remain largely unidentified. PGI/AMF is shown here to exhibit fibronectin (FN)-dependent cell surface association at both neutral and acid pH. Direct PGI/AMF binding to FN and fluorescence resonance energy transfer (FRET) between PGI/AMF and FN were detected only at pH 5. At neutral pH, the interaction of PGI/AMF with FN is receptor-mediated requiring prior clathrin-dependent endocytosis. PGI/AMF and FN do not co-internalize and PGI/AMF undergoes a second round of endocytosis upon recycling to the plasma membrane indicating that recycling PGI/AMF receptor complexes associate with FN fibrils. Heparan sulphate does not affect cell association of PGI/AMF at neutral pH but enhances the FN-independent cell surface association of PGI/AMF at acid pH identifying two distinct mechanisms for PGI/AMF sequestration under acidic conditions. However, only PGI/AMF sequestration by FN at acid pH was able to stimulate cell motility upon pH neutralization identifying FN as a pH-dependent cytokine trap for PGI/AMF. The multiple ways of cellular association of PGI/AMF may represent acquired mechanisms to regulate and harness the cytokine function of PGI/AMF.