Cevdet Ozdemir

Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial

Background In children, the clinical efficacy and immunological mechanisms of sublingual immunotherapy (SLIT) compared with subcutaneous immunotherapy (SCIT) is still to be elucidated.

T regulatory cells and their counterparts: masters of immune regulation

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen‐specific CD4+ T‐helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen‐specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen‐specific T cell proliferation and the suppressed secretion of Th1 and Th2‐type cytokines. Treg cells are able to inhibit the development of allergen‐specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.

Efficacy of long-term sublingual immunotherapy as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma

Although sublingual immunotherapy (SLIT) is accepted to be a viable alternative of specific‐allergen immunotherapy, the efficacy of long‐term SLIT in asthmatic children is not well established. The efficacy of 3 yr of SLIT in addition to pharmacotherapy was compared with pharmacotherapy alone in a prospective, open, parallel‐group, controlled study. Children with asthma aged 4–16 yr, sensitive to house dust mite (HDM) were followed up for a run‐in period of 1 yr and then grouped as those who would receive SLIT + pharmacotherapy (n = 62) or pharmacotherapy alone (n = 28). All patients were evaluated based on symptom‐medication scores and lung function tests every 3 months, as well as skin‐prick test and serum total immunoglobulin E (IgE) levels annually for 3 yr. Children in the SLIT + pharmacotherapy group demonstrated significantly lower mean daily dose and annual duration of inhaled corticosteroid (ICS) usage when compared with controls. At the end of the 3 yr, within‐group comparisons revealed statistically significant decreases in the dose and duration of ICS only in the SLIT group. Furthermore, 52.4% of subjects in the SLIT + pharmacotherapy group were able to discontinue ICS treatment for at least 6 months, which was only 9.1% for the pharmacotherapy group. Three years of SLIT as an adjunct to pharmacotherapy resulted in reduction of both the duration and dose of ICSs and successful discontinuation of ICSs along with improvement in lung functions in HDM‐allergic children with asthma.

Mechanisms of immunotherapy to wasp and bee venom

Hymenoptera venoms are important allergens that can elicit both local and systemic allergic reactions, including life‐threatening anaphylaxis. Venom immunotherapy (VIT) remains the most effective treatment, reducing the risk of systemic reactions in individuals with Hymenoptera venom allergy. VIT can restore normal immunity against venom allergens and provide patients with a lifetime of tolerance to venoms. During VIT, peripheral tolerance is induced by the generation of allergen‐specific regulatory T (Treg) cells, which suppress proliferative and cytokine responses against the venom allergens. Treg cells are characterized by IL‐10 secretion that directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. Treg cells also have influence on B cells, suppressing IgE production and inducing the production of blocking type IgG4 antibodies against venom allergens. An accumulating body of evidence suggests that Treg cells may affect allergen sensitization and methods for enhancing this cell population may eventually improve the efficacy of VIT. In this article, immune mechanisms enrolled in bee and wasp VIT are reviewed.

Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring

The treatment of dyspeptic disorders with anti‐acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30–50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti‐acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti‐acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish‐specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensi‐tization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these off‐spring we found a relative Th2‐dominance, because the Thl‐ and T‐regulatory cytokines were significantly sup‐pressed. Our data provide evidence that the anti‐acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2‐milieu in their offspring. From these results we propose that anti‐acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants.—Schöll, I., Ackermann, U., Özdemir, C., Blümer, N., Dicke, T., Sel, S., Sel, S., Wegmann, M., Szalai, K., Knittelfelder, R., Untersmayr, E., Scheiner, O., Garn, H., Jensen‐Jarolim, E., Renz, H. Anti‐ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2‐bias in their offspring. FASEB J. 21, 1264–1270 (2007)

T-Cell Response to Allergens

Anaphylaxis is a life-threatening IgE-dependent type 1 hypersensitivity reaction in which multiple organ systems are involved. The existence of allergen exposure and specific IgE are the major contributors to this systemic reaction. The decision of the immune system to respond to allergens is highly dependent on factors including the type and load of allergen, behavior and type of antigen-presenting cells, innate immune response stimulating substances in the same micromilieu, the tissue of exposure, interactions between T and B lymphocytes, costimulators, and genetic propensity known as atopy. Antigen-presenting cells introduce processed allergens to T-helper lymphocytes, where a decision of developing different types of T-cell immunity is given under the influence of several cytokines, chemokines, costimulatory signals and regulatory T cells. Among Th2-type cytokines, interleukin (IL)-4 and IL-13 are responsible for class switching in B cells, which results in production of allergen-specific IgE antibodies that bind to specific receptors on mast cells and basophils. After re-exposure to the sensitized allergen, this phase is followed by activation of IgE Fc receptors on mast cells and basophils resulting in biogenic mediator releases responsible for the symptoms and signs of anaphylaxis. Since the discovery of regulatory T cells, the concepts of immune regulation have substantially changed during the last decade. Peripheral T-cell tolerance is a key immunologic mechanism in healthy immune response to self antigens and non-infectious non-self antigens. Both naturally occurring CD4+CD25+ regulatory T (Treg) cells and inducible populations of allergen-specific, IL-10-secreting Treg type 1 cells inhibit allergen-specific effector cells and have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. On the other hand, Th17 cells are characterized by their IL-17 (or IL-17A), IL-17F, IL-6, tumor necrosis factor-alpha, and IL-22 expressions, which coordinate local tissue inflammation through upregulation of proinflammatory cytokines and chemokines. This chapter is mainly focused on antigen presentation pathways and allergen-specific T-cell responses.

Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma

Background Therapeutic modalities of asthma have not been proved to be successful in reversing the already established chronic changes of airways.

Treatment with chitin microparticles is protective against lung histopathology in a murine asthma model

Background Chitin, a natural polysaccharide extracted from shrimp, is a potent T and B cell adjuvant when delivered in the form of chitin microparticles and can shift a polarized T‐helper type 2 (Th2) immune response towards a Th1 response.

Specific immunotherapy and turning off the T cell: how does it work?

OBJECTIVE To examine T-regulatory (Treg) cell functions in allergic immune responses and their roles during allergen specific immunotherapy based on recent developments and current understanding of immune regulation. DATA SOURCES PubMed search of English-language articles regarding Treg cells and allergen specific immunotherapy. STUDY SELECTION Articles on the subject matter were selected and reviewed. RESULTS Allergen specific immunotherapy is the ultimate treatment modality targeting the immunopathogenic mechanisms of allergic disorders. A diminished allergen-specific T-cell proliferation and suppressed secretion of T(H)1- and T(H)2-type cytokines are the characteristic hallmarks. In addition, Treg cells inhibit the development of allergen-specific T(H)2 and T(H)1 cell responses and therefore exert key roles in healthy immune response to allergens. Treg cells potently suppress IgE production and directly or indirectly control the activity of effector cells of allergic inflammation, such as eosinophils, basophils, and mast cells. CONCLUSION As advancements in the field of allergen specific immunotherapy ensue, they may provide novel progression of more rational and safer approaches for the prevention and treatment of allergic disorders. Currently, the Treg cell field is an open research area to increase our understanding in mechanisms of peripheral tolerance to allergens.

Comparison of Der p1-specific antibody levels in children with allergic airway disease and healthy controls

Although children, with allergic airway disease, who are sensitized to house‐dust mite (HDM) are known to have increased levels of allergen‐specific IgE and IgG, the association between the quantity of those immunoglobulins and the clinical features of disease is not yet well established. The purpose of this study was (i) to evaluate Der p1‐specific IgA, IgG1, IgG4, and IgE levels of children with HDM‐allergic asthma and allergic rhinitis and to compare it with that of healthy controls (ii) to assess the association with disease duration. A total of 73 patients were included. Of those, 58 had asthma (M/F: 27/31, mean age 7.9 ± 2.7 yr) and 15 were diagnosed as allergic rhinitis (M/F: 8/7, mean age 10.1 ± 4.0 yr) without asthma. Twenty‐five (M/F: 13/12, mean age 9.5 ± 4.2 yr) non‐allergic children were included as healthy controls. Data on age at onset and duration of disease were recorded. Then, Der p1‐specific IgA, IgG1, IgG4, IgE levels were measured in all of the 98 subjects by ELISA. Comparison of Der p1‐specific antibody levels of patients and controls revealed that Der p1‐specific IgG1, IgG4 and IgE levels of patients with asthma (p = 0.012, p = 0.021, p = 0.004, respectively) were significantly higher than healthy controls. Also, the ratio of Der p1‐specific IgA/IgE was significantly lower in asthmatic children when compared with children with allergic rhinitis and controls (p = 0.029, p < 0.001, respectively). Der p1‐specific IgG1, IgG4, IgE and IgA levels of asthmatic children with duration of disease of ≥4 yr were significantly higher than those with disease duration of <4 yr. IgA/IgE ratio was not significantly different in those two groups of asthmatics. We concluded that although all of the specific antibody levels increased with longer duration of asthma, IgA/IgE ratio remains to be low in asthmatic children allergic to HDM.