Effect of Ingested Interferon-�� on ��-Cell Function in Children With New-Onset Type 1 Diabetes

OBJECTIVE

To evaluate the safety and efficacy of ingested human recombinant interferon-α (hrIFN-α) for preservation of β-cell function in young patients with recent-onset type 1 diabetes.

RESEARCH DESIGN AND METHODS

Subjects aged 3–25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-α at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal.

RESULTS

Individuals in the placebo group (n = 30) lost 56 ± 29% of their C-peptide secretion from 0 to 12 months, expressed as area under the curve (AUC) in response to a mixed meal. In contrast, children treated with hrIFN-α lost 29 ± 54 and 48 ± 35% (for 5,000 [n = 27] and 30,000 units [n = 31], respectively, P = 0.028, ANOVA adjusted for age, baseline C-peptide AUC, and study site). Bonferroni post hoc analyses for placebo versus 5,000 units and placebo versus 30,000 units demonstrated that the overall trend was determined by the 5,000-unit treatment group. Adverse events occurred at similar rates in all treatment groups.

CONCLUSIONS

Ingested hrIFN-α was safe at the doses used. Patients in the 5,000-unit hrIFN-α treatment group maintained more β-cell function 1 year after study enrollment than individuals in the placebo group, whereas this effect was not observed in patients who received 30,000 units hrIFN-α. Further studies of low-dose ingested hrIFN-α in new-onset type 1 diabetes are needed to confirm this effect.Residual β-cell function was shown to correlate with decreased complication rates in the Diabetes Control and Complications Trial (1). As a result, preservation of β-cell function is an important treatment goal in patients with type 1 diabetes. Over the past 25 years, multiple clinical trials attempted to prevent progressive β-cell destruction after the diagnosis of type 1 diabetes using immunosuppressive or immunomodulatory agents such as cyclosporin (2,3), cyclosporin in combination with bromocriptine (4), azathioprine with or without glucocorticoids (5,6), nicotinamide with or without glucocorticoids (7,8), and parenteral interferon-α (IFN-α) (9). More recent intervention trials used monoclonal antibody–based therapies such as rituximab (anti-CD-20) (clinical trial reg. no. NCT00279205), daclizumab (anti-CD25) in combination with mycophenolate mofetil (clinical trial reg. no. {"type":"clinical-trial","attrs":{"text":"NCT00100178","term_id":"NCT00100178"}}NCT00100178), anti-CD3 (10–12), and GAD (13). Although several studies are still ongoing and thus the results are pending, trials of anti-CD3 antibodies and GAD have demonstrated delayed decline of endogenous insulin secretion. However, none of these intervention trials have yet been translated into common clinical practice for two reasons: 1) the β-cell protective effect has been temporary, and 2) some of the agents available were associated with unacceptable side effects, such as impairment of renal function in the case of calcineurin inhibitors.The original observation that ingested type 1 interferon has an immunomodulatory effect was made in mice with chronic relapsing experimental autoimmune encephalomyelitis (14). Subsequently, a phase I trial demonstrated that 10,000–30,000 but not 100,000 units ingested IFN-α act as a biological response modifier without apparent toxicity in humans with multiple sclerosis (15), and a phase II trial suggested that 10,000 units may be more clinically effective than 30,000 units (16). The mechanism of action remains unclear. It is thought that ingested interferon, which is acid stable and therefore resists gastric digestion, binds to high-affinity receptors in the gut-associated lymphoid tissue where it transduces its signal. Serum levels do not change nor do other protein markers of interferon absorption (e.g., β₂-microglobulin, neopterin, and 2-5A synthetase) (17).A decade ago, ingested INF-α was reported to modify the onset of autoimmune diabetes in a commonly used animal model, the nonobese diabetic (NOD) mouse. Adoptive transfer of unstimulated splenocytes secreting interleukin (IL)-4 and IL-10 from mouse IFN-α–fed donors suppressed spontaneous diabetes in recipients, thus demonstrating the presence of ingested IFN-α–activated regulatory splenic cell populations that work via increased IL-4 or IL-10 production (18). A small, open-label pilot project in 10 children with recently diagnosed type 1 diabetes supported the safety of ingested interferon and helped with dose finding (19). The current study is the first randomized, controlled trial testing the safety and efficacy of ingested human recombinant (hr) IFN-α to preserve β-cell function in young patients with recent-onset type 1 diabetes.