Abstract
AbstractsBackgroundRegulatory T cells (Tregs) are pivotal in immune tolerance to allergens. Low-dose IL-2 (IL-2LD) expands and activates Tregs. We assessed IL-2LDefficacy for controlling clinical responses to allergen exposures.MethodsRHINIL-2 was a phase-2a single-centre, randomised, double-blind, placebo-controlled proof-of-concept study. Twenty-four patients with allergic rhinitis to birch pollen (BP) were included, 66% having concomitant asthma. All had IgE and positive skin prick tests to BP at inclusion, and a total nasal symptom score (TNSS) ≥5 following a 4-hour nasal exposure to BP in an environmental-exposure-chamber (EEC). Patients received 1 MUI/day of IL-2 or Placebo for 5 days, followed by weekly injections for 4 weeks. Clinical responses to subsequent BP exposures in the EEC were evaluated using TNSS, the rhinitis visual analogue scale (VAS) and spirometry. The primary efficacy endpoint was the difference in TNSS area under the curve between inclusion and day 40 (TNSSΔAUC). This trial is registered withClinicalTrials.gov(NCT02424396).OutcomesIL-2LDtreatment induced a significant expansion and activation of Tregs. The TNSSΔAUC in the ILT-101 and Placebo groups was non significantly different (-8.03 vs -4.76, p=0.32). TNSS and VAS AUCs were significantly reduced from baseline to day 40 in the ILT-101 group only (p=0.04 and p=0.01 respectively). The ratio of forced expiratory volume in 1 second / forced vital capacity (FEV1P) and the forced mid-expiratory flow (FEF25-75%) showed significant improvement in the ILT-101 vs Placebo groups at day 40 (p=0.04 and 0.04 respectively). There was a significant increase in eosinophils during treatment and no severe treatment-related adverse events.InterpretationIL-2LDis well-tolerated in allergic patients, including in those with asthma. Although there was a trend towards a reduction in nasal scores, the primary endpoint was not reached in this small study. However, the short treatment duration used in this study cannot have effects on IgE levels given their half-life. Thus the limited efficacy observed suggest that Tregs mitigate allergic reactions and represent novel targets for the treatment of allergy.FundingAssistance Publique-Hôpitaux de Paris, ILTOO pharma, Agence Nationale de la RechercheResearch in the contextAllergic rhinitis (AR) is a common inflammatory disorder of the nasal mucosa, affecting millions worldwide, and often associated with asthma. Its management encompasses various strategies targeting symptom relief, such as antihistamines, corticosteroids and leukotriene receptor antagonists. Biologics targeting specific pathways, such as IgE, IL-4, IL-5, and IL-13, are in development. Curative treatment such as allergen-specific immunotherapy (AIT) for re-establishing tolerance to the allergen have limited efficacy. Despites its often moderate severity, AR can profoundly affect the quality of life and remains an unmet medical need.Treg have a clear and direct role in preventing allergy, as exemplified by the fact that their complete deficiency in the IPEX syndrome leads to allergy. The role of Treg in mitigating an existing allergy is less clearly established. It mainly comes from the observation that successful allergen-specific immunotherapy (AIT) is associated with the induction of Tregs. Of note, both a Treg defect and a positive impact of Tregs during AIT have been described for allergic rhinitis patients. Collectively, these results highlight that strategies to increase Treg numbers and/or fitness might be beneficial in the treatment of allergic rhinitis.Evidence before this studyTreg-targeted therapies have not yet been evaluated in humans with allergy. That IL-2LDhas not yet been evaluated is possibly because it triggers eosinophilia. This is due to the stimulation of innate lymphoid cells type 2 (ILC2), which express the high affinity receptor for IL-2 and produce IL-5 upon IL-2 activation, which in turn triggers the eosinophilia. Eosinophils are critical mediators in allergic responses, contributing to inflammation and tissue damage. When exposed to allergens, eosinophils release molecules, including histamines, leukotrienes, and cytokines, which contribute to tissue inflammation and allergy symptoms. Eosinophils are particularly implicated in asthma and allergic rhinitis, in which they contribute to airway hyperresponsiveness, mucus production, and remodelling. IL-5 is a key cytokine for eosinophils and monoclonal antibodies against IL-5 are currently developed. Of note, the IL-2LD-triggered IL-5-induced eosinophilia has not yet been associated with severe side effects, even in patients who have received daily IL-2LDinjections for years and had persistent eosinophilia.The added value of this studyThis is to our knowledge the first study of a Treg-targeted therapy in allergy, and of IL-2LD in allergy. It shows that, as expected, IL-2LD can directly stimulate Tregs and indirectly eosinophils in patients with allergies. The eosinophilia went up to twice the normal value and had no clinical significance, including in patients with asthma. The IL-2LD safety profile in this double-blind placebo control study relieves the concerns of using it in allergy, and thus license its further clinical investigation, including in asthma. Although there was a trend towards a reduction in nasal scores, the primary endpoint was not reached in this small study. However, the short treatment duration used in this study cannot have effects on IgE levels given their half-life. Thus, the limited efficacy observed suggest that Tregs mitigate allergic reactions and represent novel targets for the treatment of allergy that warrants further clinical investigation in larger studies. Our study also highlights the value of EEC for studying a novel treatment of allergy.Implications of all the available evidenceThe possible improvements in the clinical response to an allergen challenge were obtained after a short treatment that stimulated Treg fitness but could not have any effects on the effector mechanisms of allergy. Thus, as they showed that Treg could mitigate ongoing allergic response, Treg represents a novel target in allergy. This opens the door for combination therapies, notably with molecules targeting the effector immune responses and with allergen-specific therapies aimed at re-establishing tolerance to the allergen.
Publisher
Cold Spring Harbor Laboratory