Dale T. Umetsu

Innate lymphoid cells and asthma

Asthma is a complex and heterogeneous disease with several phenotypes, including an allergic asthma phenotype characterized by TH2 cytokine production and associated with allergen sensitization and adaptive immunity. Asthma also includes nonallergic asthma phenotypes, such as asthma associated with exposure to air pollution, infection, or obesity, that require innate rather than adaptive immunity. These innate pathways that lead to asthma involve macrophages, neutrophils, natural killer T cells, and innate lymphoid cells, newly described cell types that produce a variety of cytokines, including IL-5 and IL-13. We review the recent data regarding innate lymphoid cells and their role in asthma.

Omalizumab facilitates rapid oral desensitization for peanut allergy

Background: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti‐IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. Objective: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. Methods: Thirty‐seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1‐day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. Results: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab‐treated subjects versus 22.5 mg for placebo‐treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty‐three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000‐mg food challenge. Overall reaction rates were not significantly lower in omalizumab‐treated versus placebo‐treated subjects (odds ratio, 0.57; P = .15), although omalizumab‐treated subjects were exposed to much higher peanut doses. Conclusion: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

Innate immunity in the lung regulates the development of asthma

The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin‐4 (IL‐4), IL‐5, IL‐13, interferon‐γ, IL‐17, and IL‐22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non‐allergic asthma phenotypes develop.

A new player on the psoriasis block: IL-17A- and IL-22-producing innate lymphoid cells

Innate lymphoid cells (ILCs) are a recently discovered family of innate immune cells belonging to the lymphoid lineage, yet lacking antigen-specific receptors. ILCs were first identified in the intestinal tract, where they contribute to epithelial barrier integrity and host responses to commensal microbes. Teunissen et al. in the current issue and Villanova et al. (JID, 134, 984-99) now suggest an important role for type 3 ILCs (ILC3s) in the skin, particularly in psoriasis. Both groups found an increased frequency of IL-22- and/or IL-17A-producing ILCs in psoriatic skin and blood. These cells are activated in response to IL-1β and IL-23, correlate with disease severity, and are decreased following anti-TNFα treatment. The presence of a novel ILC population in psoriatic skin, one that responds to biologic therapeutics, suggests that dysregulation of ILCs is a contributing factor to psoriasis pathogenesis.

Innate lymphoid cells in asthma: Will they take your breath away?

Asthma is a complex and heterogeneous disease that is characterized by airway hyper‐reactivity (AHR) and airway inflammation. Although asthma was long thought to be driven by allergen‐reactive TH2 cells, it has recently become clear that the pathogenesis of asthma is more complicated and associated with multiple pathways and cell types. A very exciting recent development was the discovery of innate lymphoid cells (ILCs) as key players in the pathogenesis of asthma. ILCs do not express antigen receptors but react promptly to “danger signals” from inflamed tissue and produce an array of cytokines that direct the ensuing immune response. The roles of ILCs may differ in distinct asthma phenotypes. ILC2s may be critical for initiation of adaptive immune responses in inhaled allergen‐driven AHR, but may also function independently of adaptive immunity, mediating influenza‐induced AHR. ILC2s also contribute to resolution of lung inflammation through their production of amphiregulin. Obesity‐induced asthma is associated with expansion of IL‐17A‐producing ILC3s in the lungs. Furthermore, ILCs may also contribute to steroid‐resistant asthma. Although the precise roles of ILCs in different types of asthma are still under investigation, it is clear that inhibition of ILC function represents a potential target that could provide novel treatments for asthma.

IL-33 Drives Augmented Responses to Ozone in Obese Mice.

Background: Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure. Objectives: We assessed the role of IL-33 in the augmented effects of ozone observed in obese mice. Methods: Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in γδ T cells and their wildtype controls. Results and Discussion: Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ γδ T cells. Ozone increased ST2+ γδ T cells, indicating that these cells can be targets of IL-33, and γδ T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines. Conclusions: Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in γδ T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246–253;u2002http://dx.doi.org/10.1289/EHP272

Oral immunotherapy and anti-IgE antibody treatment for food allergy.

Food allergy is a major public health problem affecting nearly 10 % of children in most industrialized countries. Unfortunately, there are no effective therapies for food allergy, relegating patients to simply avoid the offending foods and treat reactions that occur on accidental exposure. Recently however, studies suggest that food immunotherapy may provide a promising new approach to food allergy, particularly using the oral form of immunotherapy (OIT). Enthusiasm for this approach though must be tempered because of the significant allergic reactions that often occur with OIT that tends to limit its use to patients with less severe disease. On the other hand, recent studies suggest that concomitant treatment of patients with omalizumab (anti-IgE monoclonal antibody) during the updosing phase of OIT may greatly reduce the allergic reactions associated with OIT, even in high-risk patients. This combined method may provide a novel approach to successfully and rapidly treat a large fraction of patients with high-risk food allergy.

Targeting IgE to facilitate oral immunotherapy for food allergy: a potential new role for anti-IgE therapy?

Food allergy is a major public health problem without satisfactory treatment options. Of several new treatments being studied, oral immunotherapy (OIT) appears to be the most promising. Unfortunately, OIT is associated with an unacceptably high frequency of allergic reactions. However, recent studies suggest that OIT might be made safer and faster when performed in conjunction with anti-IgE monoclonal antibody as an adjunctive treatment.

Long-term Outcome of Peanut Oral Immunotherapy Facilitated Initially by Omalizumab

BACKGROUNDnWe successfully used omalizumab to facilitate peanut oral immunotherapy (OIT) in children with reactivity to ≤50mg peanut protein and with high peanut IgE (median, 229 kU/L).nnnOBJECTIVEnWe report on long-term OIT outcomes in these patients, including dosing changes, adverse events, peanut immunoglobulin changes, and quality of life (QoL).nnnMETHODSnPatients were followed for up to 72 months (67xa0months of maintenance). Outcomes were collected on peanut dose amount, form, and frequency, as well as adverse events, (QoL), and laboratory studies.nnnRESULTSnOf 13 patients initially enrolled, 7 patients (54%) continued on peanut OIT through month 72; 6 (46%) discontinued therapy because of adverse reactions. Maintenance peanut protein dose varied between 500 and 3500mg. Most patients consumed different peanut-containing products. All patients experienced at least 1 adverse event, and 1 patient developed eosinophilic esophagitis. Peanut-IgE, Arah1-IgE and Arah2-IgE, peanut-SPT, peanut-IgE:IgE ratio, and Arah2-IgE:Arah2-IgG4 ratio decreased on OIT. Peanut-IgG4, Arah1-IgG4, and Arah2-IgG4 initially increased on OIT and then decreased, though not falling to baseline levels. In patients who stopped OIT, there was a trend for reversal of these biomarker changes. Higher peanut-IgE and Arah2-IgE at study month 12 were associated with discontinuation. Patient and parent QoL improved from baseline, even in patients who discontinued OIT.nnnCONCLUSIONSnAlthough adjunctive omalizumab allowed for faster and successful desensitization in patients with high peanut-IgE, almost half of patients discontinued OIT within 72 months because of reactions. Patients who stopped therapy had higher month 12 peanut-IgE and Arah2-IgE. It is possible that these patients might benefit from longer omalizumab administration.

Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function

Oral immunotherapy (OIT) successfully desensitizes patients with food allergies, but the immune mechanisms mediating its efficacy remain obscure.