Immunological approaches for tolerance induction in allergy.

Allergy is the consequence of an inappropriate inflammatory immune response generated against harmless environmental antigens. In allergic disorders such as asthma and rhinitis, the Th2 mediated phenotype is a result of loss of peripheral tolerance mechanisms. In cases such as these, approaches such as immunotherapy attempt to treat the underlying cause of allergic disease by restoring tolerance. Immunotherapy initiates many complex mechanisms within the immune system that result in initiation of innate immunity, activation of both cellular and humoral B cell immunity, as well as triggering T regulatory subsets which are major players in the establishment of peripheral tolerance. Though studies clearly demonstrate immunotherapy to be efficacious, research to improve this treatment is ongoing. Investigation of allergenicity versus immunogenicity, native versus modified allergens, and the use of adjuvant and modality of dosing are all current strategies for immunotherapy advancement that will be reviewed in this article.

Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.

The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. 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 IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.

IL-10 suppresses CD2-mediated T cell activation via SHP-1.

Interleukin (IL)-10 is an essential suppressive cytokine and plays a key role in peripheral T cell tolerance to allergens, autoantigens, transplantation antigens and tumor antigens. However, the molecular mechanisms of direct T cell suppression by IL-10 are not fully understood. Here, we demonstrate that IL-10 directly inhibits CD2 signaling in T cells. T cell stimulation via CD2 alone induces activation and proliferation, when endogenous IL-10 sources are eliminated from cultures. IL-10 utilizes the src-homology-2 domain containing tyrosine phosphatase (SHP-1) to directly suppress T cell activation. The role of SHP-1 in IL-10-mediated suppression of CD2 co-stimulation on T cells is demonstrated by using dominant-negative SHP-1 over-expressing T cells and silencing endogenous SHP-1 by small inhibitory RNA. Findings are confirmed using both SHP-1-deficient mice and IL-10-deficient mice. CD2-induced proliferation is suppressed by exogenous IL-10 in IL-10-deficient, but not SHP-1-deficient murine T cells. In conclusion, SHP-1-mediated inhibition of CD2 signaling represents a novel mechanism for direct T cell suppression by IL-10.

Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy.

BACKGROUND: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. OBJECTIVE: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). METHOD: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. RESULTS: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A(2)-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-gamma and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. CONCLUSIONS: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells.

Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation.

Transforming growth factor-beta (TGF-beta) is known to mediate pleiotropic functions both inside and outside the immune system. Recent progress in this field underlines the role of TGF-beta in regulatory T (Treg) cells, where it participates in both suppression and differentiation. In addition, recent information highlights the role of TGF-beta in repair responses that lead to matrix deposition and tissue remodelling. Many chronic inflammatory diseases, such as asthma, profit from the suppression of specific immune responses by TGF-beta; however, TGF-beta-mediated tissue remodelling can be a serious complication in such diseases.

Apoptosis in tissue inflammation and allergic disease.

Genetic predisposition and environmental instructions tune thresholds for the activation, effector functions and lifespan of T cells, other inflammatory cells and resident tissue cells. Defects in apoptosis and peripheral tolerance in T cells define different allergic phenotypes. In individuals with atopic allergic disease, activated allergen-specific T cells expressing high levels of IFN-gamma predominantly undergo apoptosis in the circulation, skewing the immune response to surviving T helper type 2 (Th2) cells. In affected tissues, these cells switch on effector cytokines and induce the activation and apoptosis of epithelial cells. In individuals with non-atopic monoallergic disease, by contrast, a disturbed balance towards allergen-specific Th2 cells instead of T regulatory type 1 (Tr1) cells characterizes the T cell response.

Immune regulation by histamine.

Histamine is a potent bioamine with multiple activities in various pathological and physiological conditions. In addition to its well-characterised effects in the acute inflammatory and allergic responses, histamine regulates several aspects of antigen-specific immune response development. Histamine affects the maturation of dendritic cells and alters their T cell-polarising capacity. Histamine also regulates antigen-specific T helper 1 and T helper 2 cells, as well as related antibody isotype responses. Apparently, diverse effects of histamine on immune regulation are because of differential expression of four types of histamine receptors and their distinct intracellular signals.

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.