Mechanisms Of Allergen-specific Immunotherapy Research Articles

Allergen-specific immunotherapy induces monocyte-derived dendritic cells but attenuates their maturation and cytokine production in the lesional skin of an atopic dermatitis mouse model.

Atopic dermatitis (AD) is a common inflammatory skin disease, but current treatments for AD are mostly limited to the alleviation of symptoms and inhibition of inflammation. Allergen-specific immunotherapy (ASIT) is the only curative approach for allergic diseases and could be a promising way to cure AD. Although ASIT has been gradually applied to patients with AD, there are still few studies on its efficacy evaluation and mechanisms. Based on our previous established AD mouse model by dinitrofluorobenzene and an extract of Dermatophagoides farina, we performed ASIT on this AD model through subcutaneous injection of Dermatophagoides farina extracts to evaluate the efficacy of ASIT and study its underlying mechanisms. Our results showed that ASIT could not only alleviate skin lesions and scratching behaviors of AD mice but also inhibit their Th2-type immune responses. Furthermore, ASIT could increase the infiltration of monocyte-derived dendritic cells in skin lesions but attenuated their maturation and production of interleukin 1α and interleukin 12/23 p40. As immature and semi-mature dendritic cells preferentially induce tolerance, accumulation but inhibition of maturation of monocyte-derived dendritic cells after ASIT may indicate a novel mechanism of ASIT and a potential therapeutic target for AD.

FcεRI: A Master Regulator of Mast Cell Functions.

Mast cells (MCs) perform multiple functions thought to underlie different manifestations of allergies. Various aspects of antigens (Ags) and their interactions with immunoglobulin E (IgE) cause diverse responses in MCs. FcεRI, a high-affinity IgE receptor, deciphers the Ag–IgE interaction and drives allergic responses. FcεRI clustering is essential for signal transduction and, therefore, determines the quality of MC responses. Ag properties precisely regulate FcεRI dynamics, which consequently initiates differential outcomes by switching the intracellular-signaling pathway, suggesting that Ag properties can control MC responses, both qualitatively and quantitatively. Thus, the therapeutic benefits of FcεRI-targeting strategies have long been examined. Disrupting IgE–FcεRI interactions is a potential therapeutic strategy because the binding affinity between IgE and FcεRI is extremely high. Specifically, FcεRI desensitization, due to internalization, is also a potential therapeutic target that is involved in the mechanisms of allergen-specific immunotherapy. Several recent findings have suggested that silent internalization is strongly associated with FcεRI dynamics. A comprehensive understanding of the role of FcεRI may lead to the development of novel therapies for allergies. Here, we review the qualitatively diverse responses of MCs that impact the attenuation/development of allergies with a focus on the role of FcεRI toward Ag exposure.

Modern ideas about mechanisms of allergen-specific immunotherapy

Reviews of domestic and foreign authors consider different approaches to understanding the formation of immunological and clinical tolerance induced by allergen-specific immunotherapy (ASIT). Despite the wide variety of theoretical research, the mechanism of the bodys immune systems response to ASIT remains unclear.
 The aim of this review is to analyze the current understanding of the mechanisms of formation of changes in the bodys reactivity in response to an allergen after ASIT. It is known that the type of response to the antigen is determined by its dose. In low-dose ASIT tolerance to the antigen is formed in the absence of inflammation, which is apparently associated with the activation of specific high-affinity receptors on cells of the immune system. High doses of allergen in ASIT probably lead to a rearrangement of cellular receptors, causing a decrease in their number by internalization or a weakening of their sensitivity to an excessive signal (desensitization). Due to a decrease in the number of receptors and / or their loss of sensitivity, the response to the antigen changes according to the principle of negative regulation, implemented at the level of receptor or postreceptor mechanisms. The formation of an anti-inflammatory cytokine response to antigen contributes to the differentiation of naive T cells into inducible regulatory T cells (iTreg). The suppressing effect of Treg on immune system cells affects Th effector cells, mast cells, basophils, eosinophils, B cells, and dendritic cells.
 The occurring immunological shifts form a new type of tolerant response to the allergen, namely, the change in the type of immunoglobulins from IgE to IgG and IgA and new phenotypes of T memory and B memory cells.

Bioengineering of Virus-like Particles for the Prevention or Treatment of Allergic Diseases.

Recent findings on the mechanism of allergen-specific immunotherapy (AIT) have revisited the role of immunoglobulin G (IgG) as the development of specific blocking IgG antibodies appeared critical for the successful suppression of T-helper 2 (Th2)-biased allergic responses. Consequently, any form of molecular AIT-promoting potent allergen-specific neutralizing antibodies would be preferred to conventional administration of allergen extracts. The potent immunogenicity of virus-like particles (VLPs) could be harnessed for that purpose. The particle size (20–200 nm) optimizes uptake by antigen-presenting cells as well as lymphatic trafficking. Moreover, the display of antigens in repetitive arrays promotes potent B cell activation for the development of sustained antibody responses. The presentation of self-antigens on the particle surface was even capable to break B cell tolerance. In this review, we describe the immunomodulatory properties of the 3 VLP-based strategies designed so far for the treatment of allergic disease: VLP packaged with CpG motifs as well as chimeric particles displaying pro-Th2/Th2 cytokines or allergens (full-length or B cell epitopes).

ACTUAL CONCEPTION OF ALLERGEN-SPECIFIC IMMUNOTHERAPY MECHANISMS, POTENTIAL BIOMARKERS OF EFFICACY AND WAYS OF ENHANCEMENT

The article analyzes international position papers on the allergen-specific immunotherapy mechanisms, discusses potential biomarkers for evaluation of ASIT efficacy, as well as the perspectives for ASIT enhancement.

Application of allergen specific immunotherapy in children with allergic diseases

Allergen specific immunotherapy(AIT)is a desensitization treatment for IgE-mediated allergic diseases.Combined with pharmacological therapy, AIT is used to treat allergic asthma, allergic rhinitis and atopic dermatitis caused by allergens that cannot be avoided.AIT is the only treatment modality that can alter the natural course of allergic disease.However, because of the lack of studies, there still exists controversy about the application of immunotherapy in children with allergic diseases.The mechanism of AIT, its clinical efficacy and safety in children with allergic diseases are reviewed. Key words: Allergen specific immunotherapy; Children; Mechanism; Clinical efficacy; Safety

House Dust Mite Allergy and Associated Allergen-Specific Immunotherapy in Allergic Asthma

Allergic asthma, an important subtype of asthma endotypes, is characterized by allergen-specific and Th2 cellmediated airway inflammation. Except for pharmacologic treatment, Allergen-specific immunotherapy (ASIT) has also been considered as a potential therapy for allergic asthma. House dust mite (HDM) is a common airborne allergen among patients with allergic asthma. This review is focused on the relationship between HDM allergy and allergic asthma, underlying mechanism of ASIT, and current evidence of HDM-specific immunotherapy for allergic asthma. It was demonstrated that HDM allergy is a risk factor associated with disease development of allergic asthma. The induction of immune tolerance by regulatory T cells was proved to play a pivotal role in the immunological mechanisms of ASIT. Experimental studies in murine models of allergic asthma reveal that HDM-specific immunotherapy has not only therapeutic efficacy but also preventive potential for disease development. The clinical trials also demonstrated the efficacy of HDM-specific immunotherapy in reducing asthma symptoms and medication use. Today, the clinical application of ASIT in allergic asthma has limitation when considering the extent of benefit and systemic adverse reactions. Although sublingual immunotherapy with HDM extract was demonstrated to have better safety profile when comparing with subcutaneous immunotherapy. To make HDM-specific immunotherapy more practicable in clinical application, further advances in the development of immunotherapy and clinical trials are needed.

Human Leukocyte Antigen-G and Regulatory T Cells during Specific Immunotherapy for Pollen Allergy

Background: T_H2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G₄ blocking antibodies, a reduction in the number of effector cells, and skewing of the cytokine profile towards a T_H1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG₄). Methods: Eleven birch and/or grass pollen-allergic patients and 10 healthy nonatopic controls were studied before and during SIT. Tregs, chemokine receptors, soluble HLA-G (sHLA-G), Ig-like transcript (ILT) 2, specific IgE, and IgG₄ were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with pollen extract in vitro and immune factors were evaluated. Results: During SIT, the main changes in the peripheral blood were an increase in CXCR3⁺CD4⁺CD25⁺CD127^low/- Tregs and a decrease in CCR4⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in allergen-specific IgG₄, and a decrease in sHLA-G during the first half of the treatment period. In the PBMC in vitro experiments, the following changes were observed upon allergen-stimulation: an increase in CD4⁺CD25⁺CD127^low/- Tregs and ILT2⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in IL-10 and IL-2 levels, and an increase in sHLA-G that was most pronounced at the start of SIT. Conclusions: The changes in CXCR3⁺CD4⁺CD25⁺CD127^low/- Treg, IgG₄, and sHLA-G levels in the peripheral blood and in ILT2⁺ Treg, IL-10, IL-2, and sHLA-G levels upon in vitro allergen stimulation suggest an upregulation in immunomodulatory factors and, to some degree, a shift towards T_H1 during SIT.

Mechanisms of allergen-specific immunotherapy

Mechanisms of allergen-specific immunotherapy

Mechanisms of allergen-specific immunotherapy

Mechanisms of allergen-specific immunotherapy

Mechanisms of allergen specific immunotherapy – T‐cell tolerance and more

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific T-regulatory (Treg) cells and T helper 2 cells appears to be decisive in the development of allergic and healthy immune response against allergens. Treg cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific T helper 2 cells in allergic individuals. A decrease in interleukin (IL)-4, IL-5 and IL-13 production by allergen-specific CD4+ T cells due to the induction of peripheral T cell tolerance is the most essential step in allergen-specific immunotherapy (SIT). Suppressed proliferative and cytokine responses against the major allergens are induced by multiple suppressor factors, such as cytokines like IL-10 and transforming growth factor (TGF)-beta and cell surface molecules like cytotoxic T lymphocyte antigen-4, programmed death-1 and histamine receptor 2. There is considerable rationale for targeting T cells to increase efficacy of SIT. Such novel approaches include the use of modified allergens produced using recombinant DNA technology and adjuvants or additional drugs, which may increase the generation of allergen-specific peripheral tolerance. By the application of the recent knowledge in Treg cells and related mechanisms of peripheral tolerance, more rational and safer approaches are awaiting for the future of prevention and cure of allergic diseases.

New insights into the mechanisms of allergen-specific immunotherapy

Specific immunotherapy represents the only curative treatment of a specific allergy, and is therefore of great interest in terms of immunological mechanisms and therapeutic developments. Allergen-specific regulatory T cells are induced after the initiation of specific immunotherapy, and are assumed to suppress effector T cells directly mediating allergic inflammation. Therefore regulatory T cells may play a key role in the re-induction of allergen tolerance. Multiple pathways in many systems are described to promote or enhance regulatory T cells. This review summarizes the current view on immunological mechanisms leading to and coming from regulatory T cells. The highlighted mechanisms may not only contribute to improved specific immunotherapy, but also give insight into a clinically relevant therapy targeting regulatory T cells. The approach of addressing endogenous regulatory mechanisms specifically controlling inflammation instead of targeting inflammation itself is relevant for future pharmacological developments.

Sublingual immunotherapy: from proven prevention to putative rapid relief of allergic symptoms

Sublingual immunotherapy: from proven prevention to putative rapid relief of allergic symptoms

Mechanisms of Allergen Immunotherapy

Summary The molecular and cellular mechanisms of allergen-specific immunotherapy (SIT) have recently been investigated. It appears that, similar to a normal immune response to allergen, the generation of allergen-specific, regulatory/suppressor T cells plays a key role in succcessful SIT. T cells before and after SIT and exposure to high allergen doses, showed distinct cytokine profiles. The frequency of interleukin (IL)-10-producing T cells revealed that allergen-specific regulatory/suppressor T cells represent a dominant allergen-specific T cell subset in healthy individuals and succesful SIT. IL-10 and transforming growth factor (TGF)-β induce tolerance in T cells and regulate the specific immunity. Our results demonstrate that IL-10 and transforming growth factor (TGF)-β secreting regulatory/suppressor T cells control the healthy allergen response in cooperation with other suppressor molecules, and depletion of this T cell subset or blocking of expressed suppressor molecules, enhanced the specific response. Furthermore, IL-10 is able to generate noninflammatory IgG4 antibodies and TGF-β is a switch and promoting factor for IgA. Both cytokines suppress IgE formation. Thus, induction of specific unresponsiveness (tolerance) and development of allergen-specific regulatory CD4+, CD25+ T cells secreting IL-10 and/or TGF-β and the recovery of effector T cells by cytokines from the tissue microenvironment, represent key steps in SIT of allergy and natural immunity to allergens.

Molecular mechanisms of allergen-specific immunotherapy for atopic diseases.

Increasing prevalence of atopic diseases has become a major problem in most developing and developed countries. In the past several years, most of our studies have focused on the regulatory mechanisms of immunotherapy and exploration of novel treatment for childhood asthma, including the regulation of type 1 (TH1) and type 2 (TH2) cells, the change of cytokines and chemokines during immunotherapy and also possible novel approaches to immunotherapy in childhood atopic diseases. With further characterization of mechanisms involved in the pathogenesis of atopic diseases and immunological changes during immunotherapy, it may shed light on designing the novel treatments for atopic diseases. The data further suggested advanced immunotherapy with combined allergen and certain stimulators enhancing TH1 activity or allergen gene immunization might contribute to more efficient immunotherapy in the future.

Mechanisms of allergen specific immunotherapy

Summary Clinical efficacy of specific immunotherapy (SIT) in the treatment of respiratory allergic diseases as well as venom allergy has been demonstrated in various well-controlled studies. However the precise mechanisms of SIT have not been well defined, and for more than twenty years now, research on immunological markers of efficacy of SIT raised many theories on the mechanism of SIT. Recently, the use of molecular genetic techniques constituted a «breakthrough in the comprehension of the immunomodulatory effects of SITsince it has been demonstrated clearly that SIT induces a shift in the Th2/ Th1 balance. At the first stage there is a desensitization of effector cells like basophils, mast cells and eosinophils leading to a reduction of inflammatory mediators release. Simultaneously T lymphocytes and antigen-presenting cells are committed to the production of Th1-type cytokines although Th2-type cytokines are damped. This result in the modification of allergen-specific IgE and IgG4 production pattern and an inhibition of effector-cells migration and activation.