Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.

Areas of strength and opportunities for growth in translational science education and training: Results of a scoping review from the NCATS Education Branch.

Translational science education and training (E&T) aims to prepare the translational workforce to accelerate progress along the translational pipeline toward solutions that improve human health. In 2020-2021, the National Center for Advancing Translational Sciences (NCATS) Education Branch conducted a scoping review of the E&T literature with this focus. The review used the methodological framework proposed by Arksey and O'Malley. PubMed, Education Resources Information Center (ERIC), and Embase were searched, and forward citations conducted. Screening of titles, abstracts, and full text identified 44 included articles. Data extraction facilitated analysis of E&T content, audiences, modalities, evaluations, and recommendations. The NCATS Translational Science Principles were used to identity described or recommended E&T content. Twenty-nine articles described a translational science E&T opportunity or its evaluation, and another 15 articles offered recommendations for translational science E&T. The most prevalent NCATS Translational Science Principles were boundary-crossing partnerships (77%) and cross-disciplinary team science (75%). Among publications describing E&T opportunities, the most reported modalities were experiential learning (64%) and courses (61%) and the most reported participants were graduate students (68%) and postdoctoral fellows (54%). About half of these articles (n = 15) reported an evaluation, covering a range of proximal to distal outcomes. Recommendations emphasized the value of translational science E&T across training and career stages and the use of varied modalities to reach diverse audiences. This review highlights strengths and opportunities for growth in translational science E&T. Enhancements to content, expansion of participants and modalities, and rigorous evaluations will contribute to building a highly qualified, diverse translational science workforce.

DEIA is essential to advance the goals of translational science: Perspectives from NCATS.

The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g., morbidity, mortality) is central to NCATS' mission to deliver more interventions to all people more quickly. Working toward this goal will require enhancing diversity, equity, inclusion, and accessibility (DEIA) in the translational workforce and in research conducted across the translational continuum, to support health equity. This paper discusses how aspects of DEIA are integral to the mission of translational science (TS). It describes recent NIH and NCATS efforts to advance DEIA in the TS workforce and in the research we support. Additionally, NCATS is developing approaches to apply a lens of DEIA in its activities and research - with relevance to the activities of the TS community - and will elucidate these approaches through related examples of NCATS-led, partnered, and supported activities, working toward the Center's goal of bringing more treatments to all people more quickly.

IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice.

Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for controlling Th2 effector function remain unclear. IL-10 also has paradoxical effects on Th2-associated pathology, with IL-10 deficiency resulting in increased Th2-driven inflammation but also reduced airway hyperreactivity (AHR), mucus hypersecretion, and fibrosis. We demonstrate that increased IL-13 receptor alpha 2 (IL-13Ralpha2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10(-/-) mice. Using models of allergic asthma and chronic helminth infection, we demonstrate that IL-10 and IL-13Ralpha2 coordinately suppress Th2-mediated inflammation and pathology, respectively. Although IL-10 was identified as the dominant antiinflammatory mediator, studies with double IL-10/IL-13Ralpha2-deficient mice illustrate an indispensable role for IL-13Ralpha2 in the suppression of AHR, mucus production, and fibrosis. Thus, IL-10 and IL-13Ralpha2 are both required to control chronic Th2-driven pathological responses.

Inhibitory receptor gp49B regulates eosinophil infiltration during allergic inflammation.

gp49B, an Ig-like receptor, negatively regulates the activity of mast cells and neutrophils through cytoplasmic immunoreceptor tyrosine-based inhibition motifs. To characterize the role of gp49B further in vivo, gp49B-deficient mice were tested in two allergic models. Responses to ragweed (RW) challenge in the lung and conjunctiva were assessed in models of allergic inflammation and during an infection with parasitic larvae of the nematode Ascaris suum. Infiltration by inflammatory cells into the lung during allergic responses was under negative control of the inhibitory receptor gp49B. Furthermore, an increase in conjunctival inflammation with a predominance of eosinophils, neutrophils, and degranulated mast cells was observed in RW-sensitized, gp49B-deficient mice, which had been challenged in the eye, as compared with C57BL/6 wild-type (WT) controls. Finally, an increase in allergic inflammation in the lungs of A. suum-infected, RW-sensitized mice was observed upon RW challenge, as compared with C57BL/6 WT controls. The observed influx of eosinophils into mucus membranes is characteristic of allergic asthma and allergic conjunctivitis and may contribute to airway hyper-responsiveness, airway remodeling, and mucus production. Expression of gp49B was detected on peripheral eosinophils of control mice and on eosinophils from lungs of mice treated with RW, suggesting a role for gp49B on eosinophils in dampening allergic inflammatory responses.

Classification of ocular allergy.

PURPOSE OF REVIEW: The purpose of this article is to summarize the clinical presentations associated with the classification of ocular allergy. This article also serves to summarize recent findings of pathophysiological mechanisms associated with ocular allergy and to highlight recently improved diagnostic methods for ocular allergic inflammation. RECENT FINDINGS: The term allergic conjunctivitis may not sufficiently describe all forms of allergic eye disease, thus a new classification system is desirable, preferably derived from the varied pathophysiological mechanisms operating in the different forms of ocular allergy. Recent published material has further characterized the roles that inflammatory and structural cells have in ocular allergic inflammation. Improved diagnostic methods have also been developed to assess the underlying causes of ocular allergy. SUMMARY: The underlying immune responses of ocular allergies are complex, indicating the critical need to understand the pathophysiology behind these diseases. Extensive research over the past several years has provided valuable insight into understanding the pathophysiology associated with the different forms of allergic conjunctivitis. Further clarification of the mechanisms associated with different forms of ocular allergy is essential for improved methods of classification, diagnosis, and treatment.