Suppression of inflammation in ulcerative colitis by interferon-β-1a is accompanied by inhibition of IL-13 production

Abstract

Objective: Ulcerative colitis is associated with increased interleukin 13 (IL-13) production by natural killer T cells. Taking advantage of the inhibitory actions of interferon β on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of ulcerative colitis symptoms.

Design: Open-label interventional drug trial.

Setting: Outpatient clinical research hospital. Patients Adult patients with active ulcerative colitis (Short Clinical Colitis Activity Index (SCCAI)≥ 5). Interventions Treatment with 30 μg IM interferon-β-1a (Avonex) weekly for 12 weeks with 6 month follow-up.

Main outcome measures: Clinical response was defined as ≥ 3 point drop in the SCCAI for at least two consecutive monitoring visits, and cytokine production was measured in cultured peripheral blood and lamina propria mononuclear cells (LPMC) before and after treatment.

Results: 11 of 16 patients were clinical responders, and 4 were in remission (SCCAI ≤ 2) at the end of treatment. Rectal bleeding subscores improved dramatically by week 4 (38% with frank bleeding vs 87% pretreatment). Increased IL-13 production by LPMC T cells fell significantly in clinical responders (690 ± 99 vs 297 ± 58 pg/ml p = 0.015) but was unchanged in non-responders (542 ± 83 vs 510 ± 39 pg/ml). In addition, non-responders had significantly higher production of IL-17 and IL-6 pre-treatment compared to responders.

Conclusions: Interferon-β-1a induces clinical response and remission in a large subset of patients with ulcerative colitis that is associated with significant inhibition of IL-13 production. In addition, increased IL-17 and IL-6 production is associated with no response to interferon-β. These data provide a proof-of-concept that IL-13 is an effector cytokine in ulcerative colitis and should be a target for novel therapies.

Figure 1. A. Rate of Clinical Response to Interferon-β-1a in Ulcerative Colitis Patients

The percent of patients reporting a clinical response at specific time points (dotted line) as well as the percent of patients reporting a clinical response at any time up to a specific time point (solid line) are shown. B. Rate of Clinical Remission (SCCAI ≤ 2) to Interferon-β-1a in Ulcerative Colitis Patients. The percent of patients reporting a clinical remission at specific time points (dotted line) as well as the percent of patients reporting a clinical remission at any time up to a specific time point (solid line) are shown.

Figure 1. A. Rate of Clinical Response to Interferon-β-1a in Ulcerative Colitis Patients

The percent of patients reporting a clinical response at specific time points (dotted line) as well as the percent of patients reporting a clinical response at any time up to a specific time point (solid line) are shown. B. Rate of Clinical Remission (SCCAI ≤ 2) to Interferon-β-1a in Ulcerative Colitis Patients. The percent of patients reporting a clinical remission at specific time points (dotted line) as well as the percent of patients reporting a clinical remission at any time up to a specific time point (solid line) are shown.

Figure 2. Distribution of Rectal Bleeding Subscore Reports from the SCCAI

The bars are patterned to represent the distribution of the degree of rectal bleeding reported by patients at specific time points. The four patterns correspond to (from bottom to top), no bleeding, trace bleeding, occasionally frank, and usually frank.

Figure 3. Endoscopic Changes in Colonic Mucosa in a Patient Reporting Clinical Remission

This patient was re-treated with interferon-β-1a after experiencing relapse from a prior interferon-induced remission. The pretreatment image shows active inflammation, the 12 week image shows sharply defined shallow ulceration with less purulence, and the 24 week follow-up image shows healed mucosa 6 months after the final dose of interferon-β-1a.

Figure 4. IL-13 Production by Lamina Propria T Cells from Ulcerative Colitis patients Before and After Treatment with Interferon-β-1a

A. IL-13 in vitro secretion from anti-CD2 and anti-CD28-stimulated mucosal T cell cultures. These data represent the whole group of patients. B. Mucosal T cell IL-13 secretion according to clinical response.

Figure 5. Correlation of IL-13 Production with Ulcerative Colitis Clinical Activity

This patient received two courses of interferon-β-1a. The solid line charts the SCCAI decreasing to clinical remission (SCCAI ≤ 2) during treatment (shaded area) and follow-up and indicating a relapse of symptoms at Week 36. Serial measurements of IL-13 production (dotted line) show that it declines with induction of remission and increased in conjunction with clinical relapse.