Kimuli Ryanna

Regulatory T cells, inflammation and the allergic response-The role of glucocorticoids and Vitamin D.

Regulatory T cells (TRegs) play a central role in the maintenance of peripheral tolerance. They prevent inappropriate immune responses to ubiquitous allergens in healthy individuals, and contribute to the maintenance of immune homeostasis in the airways. Both Foxp3+ and IL-10+ TReg have been implicated in these functions. Glucocorticoids represent the mainstay of treatment for asthma and other allergic conditions, and evidence that steroids influence TReg function will be reviewed. Growing bodies of epidemiological and immunological data suggest a role for endogenous Vitamin D in immune regulation. This review will discuss the role of glucocorticoids and Vitamin D, and their potential interactions in promoting tolerance in the context of allergic disease and asthma.

Regulatory T cells in bronchial asthma.

The main focus of this review was the role of a specific subset of T cells with immunomodulatory or immunosuppressive activities, termed regulatory T cells (Tregs), in the pathogenesis and treatment of bronchial asthma. Evidence that these cells are important in maintaining immune homeostasis in health and exhibit impaired activity in active disease will be discussed. Their therapeutic potential is perhaps best highlighted by evidence that therapies with demonstrated efficacy in allergic and asthmatic disease are associated with the induction or restoration of regulatory T‐cell function, e.g. glucocorticoids, allergen immunotherapy. Strategies to improve the safety and efficacy of these treatments and that induce or boost Tregs in bronchial asthma are discussed.

Serum 25-dihydroxyvitamin D levels correlate with CD4+Foxp3+ T-cell numbers in moderate/severe asthma

impact of B-cell immunodeficiency in cases of PNP deficiency and is probably explained by the complete lack of PNP enzyme activity due to the reported nonsense mutation. Numerous symptomatic mutations, mostly missense, of the PNP gene have been identified. These mutations produce proteins with variable degrees of enzymatic activity, which correlate with the accumulation of nucleoside substrates and, to some degree, with the clinical course. It is the progressive accumulation of deoxyguanosine triphosphate in PNP deficiency that leads to progressive disease. Interestingly, similar to the progressive T-cells toxicity caused by PNP deficiency during the first years of life, the more severe B-cell defect observed in our older patient also suggests accumulating effects of PNP deficiency on B cells. Our results concur with several recent in vitro and in vivo studies describing B-cell death following PNP inhibition with excess deoxyguanosine/deoxyguanosine triphosphate concentrations, albeit at a reduced frequency compared with T-cell apoptosis. Additional studies, including longitudinal studies, are still required to determine whether B-cell function, like T-cell function, deteriorates over time in PNP-deficient patients. In normal peripheral blood B cells, the addition of deoxyguanosine leads to an inhibition of proliferation and differentiation. This effect was found to be independent of deoxyguanosine accumulation. Complete lack of PNP (as observed in our patients) triggers accumulation of deoxyguanosine, thereby disrupting B-cell development, the consequence of which is more profound with time, as indeed was found in the older sister. Another line supporting the hypothesis that the accumulation of deoxyguanosine results in global cell toxicity and that it is not restricted to T cells alone came from the use of purine and pyrimidine nucleoside analogs to treat certain malignancies, including B-cell malignancies. For example, forodesine, a PNP inhibitor, converts deoxyguanine to deoxyguanosine triphosphate and causes general apoptotic cell effect, similar to what is seen in PNP deficiency. We conclude that the variable effect on B-cell function that is observed in PNP deficiencymay be an independent event of T-cell dysfunction and that it is subject to the severity of the deficiency and the duration of the disease. Raz Somech, MD, PhD Atar Lev, MSc Amos J. Simon, PhD Suhair Hanna, MD Amos Etzioni, MD

Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma

Background Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children. Methods Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3. Results Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups—most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01). Conclusions These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.

Asthma and allergy: The early beginnings

Catherine Hawrylowicz and Kimuli Ryanna are at King’s College London, UK Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy’s Hospital, London, UK. e-mail: catherine.hawrylowicz@kcl.ac.uk or kimuli.ryanna@kcl.ac.uk asthma defined by the degree of TH2 inflammation10. These data strengthen the argument that epithelial function affects the degree of TH2 inflammation. In parallel, the clinical heterogeneity of asthma has been emphasized by unbiased statistical cluster analysis techniques. Moore et al.4 have described five distinct severe asthma phenotypes that differ in lung function, age of asthma onset, disease duration, atopy, gender, symptoms, medication use and health care usage. The existence of these distinct phenotypes suggests that several pathologic mechanisms promote the variety of symptoms. It would now be useful to analyze people with each phenotype with respect to their epithelial and immune markers to determine whether a molecular signature can be assigned to each clinical phenotype and thus provide clear direction for phenotype specific therapy. Results from recent clinical trials for a blocking antibody against the TH2 cytokine IL-5 support the presence of distinct asthma phenotypes. An effect was seen only in subjects with severe asthma resistant to standard treatments, requiring oral steroids and characterized by large numbers of eosinophils2,3. It is likely that other TH2 pathways being investigated in asthma as therapeutic targets will only be of benefit in such subjects. Those with low TH2 responses, and with high numbers of other inflammatory cells, such as neutrophils, who represent at least a third of all severe asthmatics, have a relatively poor response to steroids and thus highlight a clear unmet clinical need. Current preclinical models have focused almost exclusively on the role of TH2-derived inflammation and do not adequately characterize asthma that is not driven by TH2 responses. Developing new models is not straightforward, given that the mechanisms underlying the characteristic symptoms of non-TH2 asthma are not well understood. But research points in the direction of factors associated with the innate immune system, such as environmental exposure to bacterial endotoxin, air pollution, ozone and infection history11. The growing body of genetic and clinical data highlight the need to consider the role of structural components of the airway in the onset and propagation of asthma. In particular, the epithelium may be central, as this surface is the first contact for allergens within the lung. The environment of allergen challenge must be taken equally into consideration. To reflect the described clinical phenotypes, new models must also take into account age, obesity and gender differences, to enable investigation of how these factors affect epithelial immune interactions after allergen exposure. The task now is to refine or redesign preclinical model systems to enable more effective translation of basic science findings into the clinic.