Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.

We have proposed previously that hemopoietic myeloid progenitors contribute to the ongoing recruitment of proinflammatory cells, namely eosinophils, to sites of allergen challenge in allergic diseases such as asthma. In this study, we investigated the involvement of bone marrow-derived progenitors in the development of allergen-induced pulmonary inflammation in mild asthmatic subjects. By flow cytometry, we enumerated the level of expression of CD34, a hemopoietic progenitor cell marker, on bone marrow aspirates taken before and 24 h after allergen challenge. In addition, the coexpression of the ␣ -subunits of IL-3 receptor (IL-3R) and IL-5 receptor (IL-5R) on CD34 ϩ cells was investigated. After allergen-challenge, although no significant change in total BM CD34 ϩ cell numbers was observed, a significant increase in the proportion of CD34 ϩ cells expressing IL-5R ␣ , but not IL-3R ␣ , was detected in the 24-h post-allergen, compared with the pre-allergen bone marrow. This was associated with a significant blood and sputum eosinophilia and increased methacholine airway responsiveness, 24 h post-allergen. Using simultaneous in situ hybridization and immunocytochemistry, we colocalized the expression of messenger RNA for membrane-bound IL-5R ␣ to CD34 ϩ cells. In summary, our data suggest that increased expression of IL-5R ␣ on CD34 ϩ cells favors eosinophilopoiesis and may thus contribute to the subsequent development of blood and tissue eosinophilia, a hallmark of allergic inflammation. ( J. Clin. Invest. 1997. 100:2466-2475.)

No abstract

Introduction: Thymic stromal lymphopoietin (TSLP), an epithelial cytokine (alarmin), is a central regulator of the immune response to inhaled environmental insults such as allergens, viruses and pollutants, initiating a cascade of downstream inflammation. There is compelling evidence that TSLP plays a major role in the pathology of asthma, and therapies that aim to block its activity are in development. Areas covered:We review studies conducted in humans and human cells, largely published in PubMed January 2010-October 2019, that investigated the innate and adaptive immune mechanisms of TSLP in asthma relevant to type 2-driven (eosinophilic/allergic) inflammation and non-type 2-driven (noneosinophilic/non-allergic) inflammation, and the role of TSLP as a mediator between immune cells and structural cells in the airway. Clinical data from studies evaluating TSLP blockade are also discussed. Expert opinion: The position of TSLP at the top of the inflammatory cascade makes it a promising therapeutic target in asthma. Systemic anti-TSLP monoclonal antibody therapy with tezepelumab has yielded positive results in clinical trials to date, reducing exacerbations and biomarkers of inflammation in patients across the spectrum of inflammatory endotypes. Inhaled anti-TSLP is an alternative route currently under evaluation. The long-term safety and efficacy of TSLP blockade need to be evaluated.

We investigated the contribution of hemopoietic progenitors to the accumulation of inflammatory cells in allergic airways disease. Using a multiparameter flow-cytometric method, the detection of peripheral blood (PB) and bone marrow (BM) cells expressing CD34, a progenitor cell marker, was explored. True CD34+ blast cells were detected as a discrete cluster exhibiting low intensity CD45 expression, low granularity, and low to intermediate cell size. A significantly greater number of CD34+ cells was detected in the PB of atopic individuals (1,438 +/- 347/10(6) nonadherent mononuclear cells [NAMNC], n = 19) compared with nonatopics (236 +/- 77/10(6) NAMNC, n = 13; P = 0.006). Similarly, in BM samples, a significantly greater number of CD34+ cells was detected in atopic (17,537 +/- 4,986/10(6) NAMNC, n = 7) compared with nonatopic subjects (6,422 +/- 1,853/10(6) NAMNC, n = 13, P = 0.02). Greater numbers of total colony-forming units (CFU) (granulocyte/macrophage [GM] and Eo/Baso) were present in cultures of PB NAMNC from atopics (24 +/- 5 CFU/10(6) NAMNC) cultured with recombinant human interleukin 5 (rhIL-5) (1 ng/ml) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.003). Analyses of colony subtypes showed significantly greater numbers of IL-5-responsive Eo/Baso-CFU in cultures from atopics (15 +/- 2 CFU/10(6) NAMNC) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.011). In contrast, no significant differences in colony counts were found between the two subject groups in cultures with rhIL-3 (1 ng/ml) or rhGM-CSF (10 ng/ml). A positive correlation was observed between PB CD34+ cell numbers and total CFU in cultures with rhIL-5 (r = 0.43, n = 32, P = 0.01) and rhGM-CSF (r = 0.45, n = 32, P = 0.009). Purging BM NAMNC with an anti-CD34 monoclonal antibody completely abrogated in vitro colony growth, supporting the view that a subset of CD34+ cells represents the relevant population of progenitors growing in culture. These data indicate that flow cytometric estimation of CD34+ cells is predictive of the colony-forming capacity of the sample and may be a useful alternative tool to clonogenic assays for enumerating progenitors. In addition, raised levels of CD34+ cells and IL-5-responsive Eo/Baso-CFU in atopics, including patients with atopic asthma, indicate a role for progenitors in allergic airways disease.