Targeting key proximal drivers of type 2 inflammation in disease

Key Points Type 2 inflammation, which encompasses systemic T helper 2 (T H 2)-type responses, is emerging as a unifying feature of both classically defined allergic diseases such as asthma and a range of other inflammatory diseases. Although immunological diseases may appear disparate based on their distinct organ or tissue manifestations, the tendency for diverse allergic diseases to present as co-morbidities or progressively suggests that they may share common underlying drivers. The proximal type 2 cytokines interleukin-4 (IL-4), IL-5 and IL-13, produced by both innate and T H 2 cells, contribute to the hallmarks of type 2-driven diseases, such as elevated immunoglobulin E (IgE) production and systemic and tissue-infiltrated eosinophilia. Early clinical studies in asthma targeting IL-4, IL-5 and IL-13 did not lead to clear efficacy, possibly owing to the molecular properties of the blockers, route of administration, bioavailability and/or incorrect study patient population. However, these studies contributed to a growing understanding of the heterogeneity of asthma that led to the successful targeting of IL-4, IL-5 and/or IL-13 in subsets of patients with high biomarkers of type 2 inflammation. Probing the molecular underpinnings of atopic dermatitis also revealed prominent type 2 inflammation. Although targeting IgE or IL-5 alone did not show clinical effects in atopic dermatitis, dual blockade of IL-4 and IL-13 demonstrated significant efficacy, confirming that type 2 inflammation mediates atopic dermatitis. The success of systemic IL-4 and IL-13 blockade across three allergic diseases with disparate specific tissue manifestations — asthma, atopic dermatitis and chronic sinusitis with nasal polyps — suggests that the IL-4–IL-13 pathway is a key central driver pathway in immunological diseases. Rather than defining atopic diseases by their apparent tissue manifestations, the identification of driver pathways in these three diseases suggests that immunological diseases can be defined and grouped based on their driver immunological pathways to enable tailored therapy. Inflammatory conditions such as asthma, atopic dermatitis and chronic sinusitis with nasal polyps are caused by type 2 inflammation. In this Review, Gandhi et al . explore the idea that these conditions can be treated by targeting the common proximal drivers of type 2 inflammation, which include interleukin-4 (IL-4), IL-5 and IL-13, and discuss the supporting clinical evidence as well as ca