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Cezmi A Akdis

Publications and source records attributed to Cezmi A Akdis.

At least 19 recordsLinked to original sources
PubMed2007

Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. However, studies have indicated that more than half of human tumors exhibit TRAIL resistance. Although the mechanism of TRAIL resistance is not understood, it represents a barrier to any TRAIL-mediated gene therapy approach. In addition, no correlation between TRAIL receptor (TRAIL-R) expression profile and TRAIL resistance has been demonstrated in cancer cells. In this study, three different lung cancer cell lines and three different primary cell cultures established from patients with lung cancer (two patients with squamous cell lung carcinoma and one with adenocarcinoma) were screened for sensitivity to adenoviral delivery of TRAIL. Whereas TRAIL-resistant primary lung cell cultures and the A549 lung cancer cell line exhibited high levels of surface decoy receptor-2 (DcR2/TRAIL-R4) expression, TRAIL-sensitive lung cancer cell lines (HBE and H411) failed to express it. A DcR2 short interfering RNA (siRNA) approach involving three different siRNA constructs in combination downregulated DcR2/TRAIL-R4 expression and sensitized lung cancer cells to TRAIL-induced apoptosis. Immunohistochemical staining of samples from 10 patients with lung carcinoma suggested that high-level DcR2/TRAIL-R4 expression is a common phenotype observed in patients with non-small cell lung carcinoma.

Adenocarcinoma↗
PubMed2006

Histamine receptors are hot in immunopharmacology.

In addition to its well-characterized effects in the acute allergic inflammatory responses, histamine has been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and other functions leading to chronic inflammation. Histamine also regulates dendritic cells, T cells and B cells, as well as related antibody isotype responses. In addition, acting through its receptor 2, histamine positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The diverse effects of histamine on immune regulation appear to be due to differential expression and regulation of 4 types of histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors for histamine is highly decisive for the biological effects of histamine and drugs that target histamine receptors. This article highlights recent discoveries in histamine immunobiology and discusses their relevance in allergic inflammation.

Animals↗
PubMed2006

Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26.

The family of IL-10-related cytokines includes several human members, IL-19, IL-20, IL-22, IL-24 and IL-26, and a series of herpesviral and poxviral paralogs. Some of these cytokines share common receptor subunits. In this study, we investigated the effects of these cytokines on naive T cell differentiation, antigen-specific T cell suppression, survival ad expression of surface markers in comparison to IL-10 and cytomegalovirus (CMV)-IL-10. Human CD45RA(+) T cells were stimulated in the presence of IL-10-family cytokines in sequential 12-day cycles. After three to four cycles of stimulation, IL-10 and CMV-IL-10 led to increased IFN-gamma and IL-10 but decreased IL-4 and IL-13. Interestingly, long-term exposure of T cells to IL-19, IL-20 and IL-22 down-regulated IFN-gamma but up-regulated IL-4 and IL-13 in T cells and supported the polarization of naive T cells to Th2-like cells. In contrast, neutralization of endogenous IL-22 activity by IL-22-binding protein decreased IL-4, IL-13 and IFN-gamma synthesis. The antigen-specific suppressor activity of IL-10 and CMV-IL-10 was not observed for any of the other IL-10-family cytokines. These data demonstrate that IL-19, IL-20 and IL-22 may participate in T cell-mediated diseases by distinct regulation of T cell cytokine profiles.

Cell Differentiation↗
PubMed2006

T-cell subsets in the pathogenesis of human asthma.

Genetic predisposition and environmental instructions tune thresholds for activation of T cells, other inflammatory cells, and resident tissue cells in asthmatic inflammation. Selective migration of peripheral-blood T cells to the lungs, their survival and reactivation in the submucosa, and their effector functions represent sequential immunologic events. Activation-induced T-cell death and peripheral T-cell tolerance are critical events in disease pathogenesis. As a mechanism for peripheral Th2 response in atopic diseases, particularly, the high interferon (IFN)-gamma-producing Th1 compartment of activated effector T cells shows increased activation-induced cell death, skewing the immune response toward surviving Th2 cells in allergic asthma. After migration to asthmatic lung, these cells switch on effector cytokines and induce bronchial epithelial apoptosis with mainly IFN-gamma, tumor necrosis factor (TNF)-alpha, and Fas-ligand. In addition, skewing of allergen-specific effector T cells to T-regulatory cells appears to be an essential event in the control of harmful immune response induced by allergens as a possible means for remedy.

Allergens↗
PubMed2006

Bacillus Calmette-Guerin, Mycobacterium bovis, as an immunomodulator in atopic diseases.

Based on the hygiene hypothesis association between atopy and bacillus Calmette-Guerin (BCG), purified protein derivative skin test reaction, mycobacterial disease, and environmental mycobacteria are summarized. The role of mycobacterial species in the activation of the innate immune response through Toll-like receptors is mentioned. The implications and perspectives of BCG as a potential therapeutic adjuvant in atopic disease are discussed.

Adjuvants, Immunologic↗
PubMed2006

Histamine receptors in immune regulation and allergen-specific immunotherapy.

The cells involved in the regulation of immune responses and hematopoiesis express histamine receptors and secrete histamine. Histamine acting through four types of its receptors has been shown not only to affect chronic inflammatory responses but also to regulate several essential events in the immune response. Histamine signals have a role in the mechanisms of tolerance induced during allergen-specific immunotherapy (SIT), acting mainly through its receptor (HR) type 2. It positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The rationale for the concomitant use of H1 antihistamines during SIT is diverse and includes reduction of its immediate side effects as well as enhancement of mechanisms of specific tolerance and anti-inflammatory effects of vaccination.

Allergens↗
PubMed2006

Mechanisms of allergen-specific immunotherapy: T-regulatory cells and more.

Activation-induced cell death, anergy, or immune response modulation by regulatory T cells (Treg cells) are essential mechanisms of peripheral T-cell tolerance. Genetic predisposition and environmental instructions tune thresholds for the activation of T cells, other inflammatory cells, and resident tissue cells in allergic diseases. Skewing allergen-specific effector T cells to a Treg-cell phenotype seems to be crucial in maintaining a healthy immune response to allergens and successful allergen-specific immunotherapy. The Treg-cell response is characterized by an abolished allergen-specific T-cell proliferation and the suppressed secretion of T-helper 1- and T-helper 2-type cytokines. Suppressed proliferative and cytokine responses against allergens are induced by multiple suppressor factors, including cytokines such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta), and cell surface molecules such as cytotoxic T-lymphocyte antigen-4, programmed death-1, and histamine receptor 2. The increased levels of IL-10 and TGF-beta produced by Treg cells potently suppress IgE production while simultaneously increasing the production of noninflammatory isotypes IgG4 and IgA, respectively. In addition, Treg cells directly or indirectly suppress the activity of effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils. In conclusion, peripheral tolerance to allergens is controlled by multiple active suppression mechanisms on T cells, regulation of antibody isotypes, and suppression of effector cells. The application of current knowledge of Treg cells and related mechanisms of peripheral tolerance may soon lead to more rational and safer approaches to the prevention and cure of allergic disease.

Allergens↗
PubMed2006

Absence of T-regulatory cell expression and function in atopic dermatitis skin.

BACKGROUND: The role of regulatory T cells has been widely reported in the suppression of T-cell activation. A dysfunction in CD4(+)CD25(+) T-regulatory cell-specific transcription factor FoxP3 leads to immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome, often associated with atopic dermatitis. Increasing the number and activity of regulatory T cells in affected organs has been suggested as a remedy in various inflammatory diseases, including allergy. OBJECTIVE: To determine the presence and function of regulatory T cells in atopic dermatitis. METHODS: Immunohistochemistry of lesional atopic dermatitis skin and control skin conditions was used to demonstrate regulatory cells and cytokines in situ. The role of effector and regulatory T cells as well as their specific cytokines in apoptosis in human keratinocyte cultures and artificial skin equivalents was investigated. RESULTS: Human T-regulatory type 1 cells, their suppressive cytokines, IL-10 and TGF-beta, as well as receptors for these cytokines were significantly expressed, whereas CD4(+)CD25(+)FoxP3(+) T-regulatory cells were not found in lesional and atopy patch test atopic dermatitis or psoriasis skin. Both subsets of regulatory T cells suppress the allergen-specific activation of T(H)1 and T(H)2 cells. In coculture and artificial skin equivalent experiments, subsets of T-regulatory cells neither induced keratinocyte death nor suppressed apoptosis induced by skin T cells, T(H)1 cells, IFN-gamma, or TNF-alpha. CONCLUSION: A dysregulation of disease-causing effector T cells is observed in atopic dermatitis lesions, in association with an impaired CD4(+)CD25(+)FoxP3(+) T-cell infiltration, despite the expression of type 1 regulatory cells in the dermis.

Adult↗
PubMed2006

Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.

There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.

Adult↗
PubMed2006

Immunological mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of adverse reactions mediated by IgE. Approaches to address this problem include the use of modified allergens, novel adjuvants and alternative routes of administration. This article reviews the development of allergen-specific immunotherapy, our current understanding of its mechanisms of action and its future prospects.

Allergens↗
PubMed2006

Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific interleukin-4 (IL-4)-secreting T cells in allergic individuals. Allergen-specific immunotherapy can induce specific Tr1 cells that abolish allergen-induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL-10 and transforming growth factor-beta (TGF-beta) as secreted cytokines and various surface molecules, such as cytotoxic T-lymphocyte antigen 4 and programmed death-1. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors, which depend on CD28 costimulation. IL-10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3-kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL-10 and TGF-beta secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non-inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen-specific Tr1 cells can thus re-direct an inappropriate immune response against allergens or auto-antigens using a broad range of suppressor mechanisms.

Allergens↗
PubMed2006

T regulatory cells in allergy.

Activation-induced cell death, anergy and/or immune response modulation by T regulatory cells (T(Reg)) are essential mechanisms of peripheral T-cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather, represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen-specific effector T cells to T(Reg) cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen-specific immunotherapy. The T(Reg) cell response is characterized by abolished allergen-induced specific T-cell proliferation and suppressed T helper 1 (Th1)- and Th2-type cytokine secretion. The increased levels of interleukin-10 (IL-10) and transforming growth factor-Beta (TGF-Beta) that are produced by T(Reg) cells, potently suppress IgE production, while simultaneously increasing production of noninflammatory isotypes IgG4 and IgA, respectively. In addition, T(Reg) cells directly or indirectly suppress effector cells of allergic inflammation such as mast cells, basophils, and eosinophils. In conclusion, peripheral tolerance to allergens is controlled by multiple active suppression mechanisms. It is associated with regulation of antibody isotypes and effector cells to the direction of a healthy immune response and opens a window for novel therapies of allergic diseases.

Animals↗
PubMed2006

The role of histamine in regulation of immune responses.

Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. It can influence numerous functions of the cells involved in the regulation of immune response and hematopoiesis including macrophages, dendritic cells, T lymphocytes, B lymphocytes and endothelial cells. These cells express histamine receptors and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to chronic inflammation. Histamine regulates antigen-specific Th1 and Th2 cells, as well as related antibody isotype responses. Histamine acting through its receptor (HR) type 2, positively interferes with the peripheral antigen tolerance induced by T regulatory (T(Reg)) cells in several pathways. The diverse effects of histamine on immune regulation are due to differential expression and regulation of 4 histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors are highly decisive on the biological effects of histamine and agents that target histamine receptors. Although substantial evidence has been accumulated about histamine metabolism, receptors, signal transduction, physiological and pathological effects, the complex interrelationship and cross-talk by histamine, its receptors and other G-protein coupled receptors remain to be understood.

Animals↗
PubMed2006

Mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy (SIT) is the only treatment, which leads to a life-long tolerance against allergens due to restoration of normal immunity. The induction of a tolerant state in peripheral T cells represents an essential step in allergen-SIT. Peripheral T-cell tolerance is characterized mainly by suppressed proliferative and cytokine responses against the major allergens and its T-cell recognition sites. It is initiated by autocrine action of IL-10 and/or TGF-Beta, which are increasingly produced by the antigen-specific T Regulatory (T(Reg)) cells. Tolerized T cells can be reactivated to produce either of the distinct Th1 or Th2 cytokine patterns, thus directing allergen-SIT towards successful or unsuccessful treatment. T(Reg) cells directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. In addition, there is accumulating evidence that they may suppress IgE production and induce IgG4 and IgA production against allergens. By the application of the recent knowledge in mechanisms of allergen-SIT, more rational and safer approaches are awaiting in the future for the prevention and cure of allergic diseases.

Allergens↗
PubMed2005

T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases.

The identification of T regulatory (T(Reg)) cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4(+)CD25(+) T(Reg) cells and inducible populations of allergen-specific IL-10-secreting T(R)1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T(Reg) cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a T(Reg) phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-beta produced by T(Reg) cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. T(Reg) cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP-associated G protein-coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases.

Animals↗
PubMed2005

Apoptosis and loss of adhesion of bronchial epithelial cells in asthma.

BACKGROUND: Asthma is an inflammatory airway disease associated with infiltration of T cells and eosinophils, increased levels of pro-inflammatory cytokines, and shedding of bronchial epithelial cells (EC). We have recently shown that T cells and eosinophils cooperate in inducing bronchial EC apoptosis in asthma through secretion of IFN-gamma and TNF-alpha. Since EC shedding is a histologic hallmark of asthma, the intercellular junction of EC may be a target of pro-inflammatory cytokines. METHODS: Bronchial EC, cultured and exposed to IFN-gamma and TNF-alpha, were studied for the expression of adhesion molecules and apoptosis. In addition, the epithelial layer of bronchial biopsies from asthma patients was evaluated for apoptosis, shedding, and expression of adhesion molecules. RESULTS: We demonstrate that the induction of EC apoptosis is accompanied by loss of E-cadherin. In situ examination of E-cadherin in asthma revealed a reduction in its expression on EC membranes. In contrast, the in vitro and in vivo expression of beta1-integrins and intercellular adhesion molecule-1 (ICAM-1) increased on EC during asthmatic airway inflammation. CONCLUSIONS: Loss of cadherin-mediated intercellular adhesion and apoptosis could account for fragility and shedding of EC in asthma, especially since this occurs between columnar and basal EC.

Apoptosis↗