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Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals. [ABSTRACT FROM AUTHOR]

The binding of EPF to lymphocytes stimulates the release of soluble mediators, active in T cell dependent reactions, namely the rosette inhibition test and the adoptive transfer of contact sensitivity. On the basis of their ability to inhibit the delayed type hypersensitivity reaction in this latter assay, they have been classified as suppressor factors. This paper describes the identification of two EPF-induced suppressor factors. Unlike EPF which is neither species-restricted nor strain-restricted, these factors are genetically restricted in their action in the rosette inhibition test EPF-S1 (estimated Mr 14,000) is restricted to the I region of the mouse MHC, while EPF-S2 (estimated Mr 55,000) is restricted to a locus (or loci) outside the MHC. Like other antigen non-specific factors, release of these suppressor factors can be stimulated also by Con A. [ABSTRACT FROM AUTHOR]

The study of immune regulation and tolerance has been traditionally associated with self/nonself-discrimination. However, the finding that dominant tolerance, a model that puts in evidence the active role of regulatory T cells, can develop to nonself-antigens suggests that the imposition of tolerance can be context dependent. This paper reviews the emerging field of acquired immune tolerance to non-self antigens, with an emphasis on the different subsets of induced regulatory T cells that appear to specialize in specific functional niches. Such regulatory mechanisms are important in preventing the onset of allergic diseases in healthy individuals. In addition, it may be possible to take advantage of these immune regulatory mechanisms for the induction of tolerance in cases where pathological immune responses are generated to allergens occurring in nature, but also to other immunogens such as biological drugs developed for medical therapies. [ABSTRACT FROM AUTHOR]

Background: Although an immunomodulatory role for estrogens has long been demonstrated by experimental and clinical observations, the mechanism by which estrogens exert their effect on T cells has not been clearly defined. Methods: In this study we analyzed the effects of β-estradiol (E2), at its contraceptive dose, on the delayed-type hypersensitivity (DTH) to purified protein derivatives (PPD) and associated immune response in female mice. Results: E2 treatment decreased PPD-specific DTH response, which coincided with a decrease in the leukocytes numbers in the draining lymph nodes (DLN) and spleen compared with control mice. E2 treatment also suppressed the in vitro PPD-specific proliferative response of DLN and spleen cells from PPD-primed mice. The analysis of production and gene expression of cytokines by DLN cells demonstrated that E2 treatment suppressed IL-2 and IFN-γ production in response to PPD in vitro. In contrast, IL-4 and IL-10 gene expression by DLN cells of E2-treated mice, taken 24 h after in vivo restimulation of mice with PPD, was enhanced. Furthermore, we found that spleen APC from E2-treated mice failed to induce optimum proliferation of the PPD-primed T cells in response to PPD in vitro. The impaired APC function by E2 was not due to induction of suppressor cell activity because addition of the normal spleen APC to APC from E2-treated mice restored the proliferative response of the PPD-primed T cells in response to PPD. Conclusion: Our results suggest that the E2-mediated inhibition of DTH reaction is due to a combination of the down regulation of APC function and deviation of the immune response from Th1-type to Th2-type.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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Background BM4 is a novel genetically engineered variant of the major birch pollen allergen Bet v 1 that lacks the typical Bet v 1-like fold and displays negligible Ig E-binding but strong T cell-activating capacity. The aim of this study was to elucidate possible differences between BM4 and Bet v 1 in internalization, antigen processing, and presentation. Methods Proliferative responses to BM4 and Bet v 1 of peripheral blood mononuclear cells and Bet v 1-specific T-cell clones were compared. Fluorescently labeled BM4 and Bet v 1 were used to study surface binding, endocytosis, and intracellular degradation by monocyte-derived DC (md DC). Both proteins were digested by endolysosomal extracts of md DC. BM4- and Bet v 1-pulsed md DC were employed to assess the kinetics of activation of Bet v 1-specific T-cell clones and the polarization of naïve T cells. Results BM4 displayed a significantly stronger T cell-activating capacity than Bet v 1. Furthermore, BM4 showed increased surface binding and internalization as well as faster endolysosomal degradation compared with Bet v 1. BM4-pulsed md DC induced enhanced proliferative responses at earlier time-points in Bet v 1-specific T-cell clones and promoted less IL-5 production in T cells than Bet v 1-pulsed md DC. Conclusion The loss of the Bet v 1-fold changes the protein's interaction with the human immune system at the level of antigen-presenting cells resulting in altered T-cell responses. By combining low Ig E-binding with strong and modulating T cell-activating capacity, BM4 represents a highly interesting candidate for specific immunotherapy of birch pollen allergy. [ABSTRACT FROM AUTHOR]

In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (Tregs) include natural or thymic-derived Tregs, T-cells which express Foxp3+CD25+CD4+ and can suppress immune responses to autoreactive T-cells, as well as inducible Tregs, that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible Tregs include TH3 cells, Tr1 cells, and Foxp3+-inducible Tregs. Tregs have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4+CD25+ Tregs from mice resulted in the development of multi-organ autoimmune diseases. CD4+CD25+ Tregs and/or IL-10-producing Tr1 cells are capable of suppressing or attenuating TH2 responses to allergens. Moreover, adoptive transfer of CD4+CD25+ Tregs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing Tr1 cells as well as FoxP3- expressing IL-10 T-cells, with resulting suppression of the TH2 cytokine milieu. Activation, expansion, or suppression of CD4+CD25+ Tregs in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases. [ABSTRACT FROM AUTHOR]

β-(1,3)-Glucan is present in mould cell walls and frequently detected in house dust mite (HDM) faeces. β-Glucan exposure is thought to be associated with pulmonary allergic inflammation in mouse and man, although the published data are inconsistent. Here, we show that highly purified β-glucan exacerbates HDM-induced eosinophilic, T helper 2 type airway responses by acting as an adjuvant, promoting activation, proliferation and polarisation of HDM-specific T cells (1-Derβ T cells). We therefore provide definitive evidence that β-glucan can influence allergic pulmonary inflammation. [ABSTRACT FROM AUTHOR]

The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self-antigen recognition and dangerous autoimmune reactions. Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery. The control of self-reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self-peptides expressed at the thymic level by means of promiscuous gene expression. Self-reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells. Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body. Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders. Abnormal or excessive Th effector responses are regulated by different mechanisms. Redirection or immune deviation of Th1- or Th2-dominated responses is provided by cytokines [interferon-γ (IFN-γ) vs. interleukin-4 (IL-4)] produced by the same cell types and by the CXCR3-binding chemokines CXCL4 and CXCL10. Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-β (TGF-β). Finally, TGF-β1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL-6 contributes to the development of Th17 cells, but inhibits Treg cells. The development of Th17 cells is also down-regulated by IL-4 produced by Th2 cells and by IFN-γ produced by Th1 cells. [ABSTRACT FROM AUTHOR]

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-β (TGF-β) 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-β 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. [ABSTRACT FROM AUTHOR]

Background: Epicutaneous (EC) immunization with protein antigens has been shown to induce antigen nonspecific suppression of subsequent T cell-dependent contact hypersensitivity (CS) reactions after active immunization. The aim of this work was to test if EC application of Toll-like receptor (TLR) ligands together with protein antigen could reverse suppression of CS. Methods: Mice were EC immunized by applying gauze patches soaked with a solution of protein antigen alone or in the presence of crude bacterial material (bacterial lysates or heat-killed bacteria) or purified TLR ligands and then tested for CS response. To test if reversal of EC-induced suppression is antigen-specific, mice were patched with TNP- or OX-substituted mouse Ig alone or together with LPS and then tested for CS with corresponding or non-cross-reacting hapten. Influence of EC immunization on cytokine production by lymph node cells was measured by ELISA. Results: EC immunization with protein antigen induces antigen nonspecific suppression that can be reversed by crude bacterial material as well as purified TLR-2, TLR-3, TLR-4, and TLR-9 ligands. The effect of TLR-4 ligand LPS was not observed in the Tlr-4 mutant C3H/HeJ mouse, indicating that this effect was dependent upon intact TLR-4 signaling. Unlike the antigen nonspecific suppression of CS by EC immunization with antigen alone, the reversal of suppression by TLR ligands was specific for the protein antigen applied in the EC protocol. Conclusions: Our results strongly suggest that EC immunization with protein antigen together with TLR ligands induces a particular antigen-specific cell population, akin to previously described contrasuppressor cells, which protects immune cells against the action of suppressor cells but have no direct influence on antigen nonspecific suppressor cells induced by antigen alone. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Allergic diseases are caused by aberrant T-helper-2 immune responses in susceptible individuals. Both naturally occurring CD4(+)CD25(+) regulatory T cells and inducible populations of antigen-specific interleukin-10-secreting regulatory T cells inhibit these inappropriate immune responses in experimental models. This article discusses the evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatory T-cell generation. Current research strategies seek to exploit these observations to improve the generation of allergen-specific regulatory T-cell populations with the potential to provide the safe and long-term alleviation of disease symptoms. [ABSTRACT FROM AUTHOR]

The common marmoset (Callithrix jacchus jacchus) is a member of the Callithrichinae, a family of outbred New World primates with limited MHC polymorphisms and a propensity to develop spontaneous or experimentally induced autoimmunity. C. jacchus marmosets are susceptible to experimental allergic encephalomyelitis (EAE), and spontaneously develop autoimmune colitis and thyroiditis. Such disease models approximate the complexity of human autoimmune disorders, and allow an investigation of the respective roles of T-cell and antibody responses to self-antigens in outbred species. A key issue for further definition of the pathogenic antibody responses in human autoimmunity is to understand the diversity of the immunoglobulin repertoire in primate models. Here, we characterized the expressed immunoglobulin IGHV repertoire of the C. jacchus marmoset. Six IGHV subgroups were identified which show a high degree of sequence similarity to their human IGHV counterparts (IGHV1, IGHV3, IGHV4, IGHV5, IGHV6, and IGHV7). As in the expressed human IGHV repertoire, the framework regions are more conserved when compared to the complementarity-determining regions (CDRs), with the greatest degree of variability located in CDR3. Predicted structural features are highly conserved between C. jacchus and human IGHV. This information now provides a framework for studies of the antigen-specific repertoire of pathogenic antibodies in EAE and other immune-mediated diseases. [ABSTRACT FROM AUTHOR]

The article focuses on strategies for modulating immunoglobulin E (IgE) synthesis. The presentation of specific antigen in a non-immunogenic form is able to induce non-responsiveness and may allow selective inactivation of T cells due to the clonal distribution of the TCR. If the disease-associated T cells that induce IgE production recognize only a limited array of determinants then this may present as an approach for the down-regulation of specific responsiveness, but structural modification of the epitopes may be necessary to remove any potential IgE binding.

Leishmania major specific murine T cell blasts and clones maintained in vitro were tested for their ability to adoptively transfer delayed type hypersensitivity (DTH) reactions to normal mice. These effector cells exhibited a Lyt 1±2" cell surface phenotype. They induced specific DTH reactions in syngeneic DBA/2 mice after local transfer in the footpad, (together with parasite antigens) or intravenous injection followed by challenge with parasite antigens in the footpad. The DTH reactions were specific for L. major antigens and required H-2 identity between the injected T cells (clones) and the adoptively transferred host. Using radioactively labelled T cell blasts for intravenous transfer, it was demonstrated that a large fraction of these functionally active cells localized in the spleen and footpad which had been challenged with parasite antigens. [ABSTRACT FROM AUTHOR]

X-irradiated (250 rads) A mice injected with syngeneic trinitrophenylated spleen cells (Syn-TNP-SC) developed syngeneic delayed-type hypersensitivity (Syn-DTH) after footpad challenge with syngeneic concanavalin A-induced lymphoblasts (Syn-Con A blasts), as indicated by footpad swelling and lymph-node proliferation assays. Genetic analysis with different recombinant strains of mouse revealed that the H-2Dd subregion restricts these immunological activities. A small immunogenic entity was isolated from Syn-TNP-SC extract by gel filtration and affinity chromatography with anti-Dd antibody. X-irradiated A mice injected with this antigen also generated inflammatory responses after challenge with Syn-Con A blasts. Analysis of the data obtained from the gel filtration and the affinity chromatography suggest that the Syn-DTH-stimulating antigen is a fragment of the H-Dd heavy chain with a molecular weight (MW) of 5,000 to 10,000. This fragment does not contain TNP molecules or sugar moieties and neither does it express affinity for antibodies against class 11 products. Ltk- cells transfected with the H-2Dd gene also induced Syn-DTH in X-irradiated A mice, while the parent cells failed to stimulate such a response. Taken together these findings indicate that the selection process in the thymus is not absolute and T cells recognizing self-major histocompatibility complex (MHC) products do migrate from this organ to the periphery of the immune system. The possible biological significance of these autoreactive cells is discussed. [ABSTRACT FROM AUTHOR]

in order to define the antigenic properties necessary for sustained allergic arthritis, we prepared a range of differently charged bovine serum albumin (BSA) species with increasing isoelectric points (4.5, 4.5-7.4, 7-8, 85-9 and >9). The highly cationic BSA >9 appeared to be in a polymeric form. We investigated three properties of these proteins: (i) antigen retention, (ii) T-cell reactivity, and (iii) arthritis induction. Injection of the respective radiolabelled antigens in the knee-joints of immunized mice showed that antigen retention increased with cationicity of the proteins, with the best retention found for ESA with pI>9. However, sustained joint inflammation was only found with BSA859, and not with a level RSA of lower or even higher pI T-cell reactivity in vivo as measured by delayed-type hypersensitivity (skin testing) was similar for the tested antigens, with the exception of polymeric BSA (>9). The latter appeared to be a poor antigen. In vitro, T-cell reactivity ([³H]- thymidine incorporation) against the cationized BSA species was slightly higher as compared to native BSA. The combination of excellent antigen retention and adequate T-cell reactivity appears to be optimal for the induction of chronic arthritis. [ABSTRACT FROM AUTHOR]

Asthma is widely recognized as an inflammatory airway disease driven by activation of Th2-type T lymphocytes in both atopic allergic and intrinsic or non-allergic forms. Recent advances in author understanding of the control of the immunological process have identified regulatory suppressive T cells which can prevent activation of self-reactive or pathological T cells in autoimmune or infectious disease models. CD4+CD25+ T cells do not proliferate in vitro in many systems, it has recently been shown that human cells can be expanded in response to antigen and CD4+CD25+ T cells do proliferate upon in vivo transfer to mice.