Epicutaneous immunization with hapten-conjugated protein antigen alleviates contact sensitivity mediated by three different types of effector cells (original) (raw)
Related papers
European Journal of Immunology, 1997
In the induction of contact hypersensitivity (CH) to an epicutaneously applied hapten, we have previously proposed that low doses of hapten sensitize primarily through epidermal Langerhans' cells (LC), whereas high doses rely largely on dermal antigen-presenting cells (APC). To examine this issue further, we applied either high or low doses of dinitrofluorobenzene (DNFB) epicutaneously to mice. We observed reduced LC density at the site after 12 h (nadir), which returned to normal levels at 24 h only after a low dose of hapten. When a low dose of an unrelated hapten, oxazolone, was painted on skin that had been painted 12 h previously with high dose of DNFB, oxazolone-specific CH was impaired. When grafts of whole skin, dermis alone, and epidermis alone prepared from skin painted 2 h previously with low or high doses of DNFB were placed onto naive, syngeneic mice, CH was induced by whole skin after both types of doses, by epidermis only after a low dose, and by dermis only after high dose. When epidermal cell suspensions were derivatized in vitro with low or high doses of DNFB, only cells exposed to a low dose induced proliferation of hapten-specific T cells. Thus, only a low dose of hapten reveals the APC functions of LC without the participation of dermal APC.
Journal of Investigative Dermatology, 2003
Allergic contact dermatitis is a T cell-mediated delayed type hypersensitivity reaction that occurs upon hapten challenge in sensitized individuals. The in£ammatory response in classical allergic contact dermatitis requires both a sensitization phase and an elicitation phase responsible for the recruitment and activation of speci¢c T cells at the site of hapten skin challenge. Conversely, previously unsensitized patients may develop a ''primary allergic contact dermatitis'' after the ¢rst skin contact with potent contact sensitizers leading to a skin in£ammation with all the features of classical allergic contact dermatitis. In this study we used an experimental murine model, referred to as contact hypersensitivity, to study the pathophysiology of primary allergic contact dermatitis and its relationship to classical allergic contact dermatitis. We show that one epicutaneous application of a nonirritant dose of hapten (2,4-dini-tro£uorobenzene, £uorescein isothiocyanate) was su⁄cient to induce an optimal allergic contact dermatitis reaction at the site of primary contact with the hapten without subsequent challenge. As in classical allergic contact dermatitis, the skin in£ammation in primary allergic contact dermatitis was mediated by interferonc producing, CD8 þ e¡ector T cells that were induced in the draining lymph nodes at day 5 postsensitization and downregulated by CD4 þ T cells. Reverse transcriptionp olymerase chain reaction analysis revealed that the primary allergic contact dermatitis reaction was mediated by a recruitment of CD8 þ T cells at the sensitization skin site at day 6 postsensitization. Analysis of the fate of the hapten £uorescein isothiocyanate applied once on the skin revealed its persistence in the epidermis for up to 14 d after skin painting. These results suggest that the development of primary allergic contact dermatitis (i.e., without secondary challenge) is associated with persistence of the hapten in the skin, which allows the recruitment and activation of CD8 þ Tcells at the site of the single hapten application. Key words: contact hypersensitivity/hapten persistence/leukocyte tra⁄cking/skin. J Invest Dermatol 120: 641^647, 2003 A llergic contact dermatitis (ACD), one of the most common skin diseases with a great socio-economic impact, is a T cell-mediated in£ammatory reaction occurring at the site of challenge with a contact allergen (hapten) in sensitized individuals . Knowledge of the pathophysiology of ACD is derived chie£y from animal models in which the skin in£ammation induced by hapten painting of the skin is referred to as contact hypersensitivity (CHS) (Garrigue et al,1 9 9 4 ;V a n D e rV a l k , 2002). ACD and CHS are thus considered as synonymous and de¢ne a hapten-speci¢c T cell-mediated skin in£ammation. They represent a form of delayed type hypersensitivity reactions. As in all delayed type hypersensitivity reactions, the pathophysiology of ACD consists classically of two distinct phases, i.e., the sensitization and the elicitation phases, which are considered to be temporally and spatially dissociated . The sensitization phase (also referred to as the a¡erent phase of ACD) occurs at the ¢rst contact of skin with the hapten. Hapten is taken up by skin dendritic cells (DC) that migrate to the draining lymph nodes (LN), where they present haptenated peptides on major histocompatibility complex class I and II molecules resulting in the induction of hapten-speci¢c CD8 þ and CD4 þ T cells, respectively . The sensitization step lasts 8^15 d in humans, 5^7 d in the mouse, and is thought to have no clinical consequence. The elicitation phase, also known as e¡erent phase or challenge phase of CHS. Challenge with the same hapten in sensitized individuals leads in a few hours to the appearance of ACD. Upon subsequent contacts of the skin with the hapten, e¡ector T lymphocytes are recruited and activated in the dermis, and trigger the in£ammatory process responsible for the cutaneous lesions. This e¡erent phase of CHS takes 72 h in humans, and 24^48 h in the mouse. The in£ammatory reaction persists during several days and progressively decreases upon physiologic downregulating mechanisms. Although in some experimental systems CD4 þ
Effector and regulatory mechanisms in allergic contact dermatitis
Allergy, 2009
Contact dermatitis is a common inflammatory skin disease in industrialized countries with a great socioeconomic impact. It is one of the most common occupational diseases (1, 2). As the outermost barrier of the human body, the skin is the first to encounter chemical and physical factors from the environment. Two main types of contact dermatitis may be distinguished, according to the pathophysiological mechanisms involved: (i) irritant contact dermatitis is the expression of the proinflammatory and toxic effects of xenobiotics able to activate the skinÕs innate immune system and (ii) allergic contact dermatitis (ACD) requires the activation of antigen (Ag)specific acquired immunity, leading to the development of effector T cells (T EFF ), which mediate the skin inflammation. ACD occurs at the site of contact with an allergen called a hapten, in sensitized individuals, and it is characterized by redness, papules and vesicles, followed by scaling and dry skin. Systemic administration of hapten to sensitized patients may possibly result in systemic ACD (3, 4).
Immunotherapy of allergic contact dermatitis
Immunotherapy, 2011
The term ‘immunotherapy’ refers to treating diseases by inducing, enhancing or suppressing immune responses. As allergy is an excessive, detrimental immune reaction to otherwise harmless environmental substances, immunotherapy of allergic disease is aimed at the induction of tolerance toward sensitizing antigens. This article focuses on the historical developments, present state and future outlook for immunotherapy with haptens as a therapeutic modality for allergic contact dermatitis. Inspired by the effectiveness of immunotherapy in respiratory allergies, attempts were undertaken at curing allergic contact dermatitis by means of controlled administration of the sensitizing haptens. Animal and human experiments confirmed that tolerance to haptens can be induced most effectively when the induction of tolerance precedes attempted sensitization. In real life, however, therapy is sought by people who are already sensitized and an effective reversal of hypersensitivity seems more diffic...
Immunological mechanisms in allergic contact dermatitis
Current opinion in allergy and clinical immunology, 2015
Allergic contact dermatitis is a skin disease resulting from an adverse reaction of the immune system to low-molecular-weight organic chemicals or metal ions. This review summarizes recent findings that highlight new details of the complex orchestration of the cellular and molecular immune response to contact allergens. Progress has been made in the characterization of the roles of natural killer T (NKT) cells, natural killer cells, mast cells and neutrophils, as well as in the elucidation of signaling pathways triggered by contact allergens. Global technologies begin to reveal gene signatures for contact allergen identification and improved diagnostics. Recent progress in contact allergy research has deepened our understanding of the molecular and cellular pathomechanisms, and opens new avenues towards improved diagnostics and treatments, as well as prevention and risk assessment strategies.
Journal of Investigative Dermatology, 2009
Allergic contact dermatitis (ACD) is mediated by hapten-specific CD8 þ T cells and downregulated by CD4 þ T cells. We have recently shown in a model of ACD to weak haptens that priming of IFNg-producing CD8 þ T cells and the development of skin inflammation could be obtained in mice deficient in CD4 þ T cells. Here we show that IFNg production by lymph node (LN) cells draining the site of skin sensitization of CD4 þ T-cell-deficient mice is a marker of the sensitizing properties of weak haptens. LN cells from mice sensitized as in the classical local lymph node assay (LLNA) were recovered at day 5, then cultured for 20 hours in the presence of submitogenic doses of phytohemagglutinin, and finally tested for the production of IFNg. Results show that: (i) production of INFg by LN cells was induced by weak and moderate allergens in a dose-dependent fashion; (ii) the magnitude of IFNg production paralleled the sensitizing properties of allergens allowing to classify them as moderate or weak haptens; (iii) chemicals without sensitizing properties were unable to stimulate IFNg production by LN cells. Therefore, the IFNg LLNA appears as a sensitive, specific, and robust assay to detect weak contact allergens.
Role of antigen-presenting cells in the development and persistence of contact hypersensitivity
Journal of Experimental Medicine, 1980
Three outcomes pertinent to contact sensitivity (CS) follow immunization with various forms of trinitrophenylated (TNP) substrates: (a) specific immunological unresponsiveness for CS is induced when immunization favors activation of splenic suppressor cells. This state is achieved by intravenous injection of trinitrophenyl-conjugated to various types of cells, such as peritoneal exudate cells (PEC). (b) A short-lived or evanescent form of CS is induced when immunization reduces activation of the suppressor circuit. This can be achieved by subcutaneous immunization with trinitrophenyl conjugated to syngeneic PEC, by pretreatment with cyclophosphamide to diminish suppression before intravenous immunization, or by altering the mode of antigen presentation by using TNP-substrate that has undergone phagocytosis. (c) A long-lived form of CS is induced when trinitrophenyl is presented to the immune system on skin cells either by contact skin painting with reactive trinitrophenyl, or by sub...
Hapten-specific T cell lines mediating delayed hypersensitivity to contact-sensitizing agents
Journal of Experimental Medicine, 1982
Continuous cultures of T cells from the lymph nodes of mice sensitized to the contact sensitizers 4-ethoxymethylene-2-phenyl oxazolone or picryl chloride have been established. For continuous proliferation, the lines required specific antigen, syngeneic antigen-presenting cells, and growth factors from the supernatant of concanavalin-A-stimulated lymphoid cultures. Cells from the lines showed antigen specificity and major histocompatibility complex restriction in proliferation assays and in delayed hypersensitivity. They could mediate delayed hypersensitivity to the sensitizer presented as a reactive hapten or coupled to keyhold limpet hemocyanin.
Specific suppressor T cells in rats active in the afferent phase of contact hypersensitivity
Cellular Immunology, 1986
The optimal conditions for the induction of contact hypersensitivity in rats and the characteristics of its suppression were studied using the sensitizing haptens dinitrotluorobenzene (DNFB) and trinitrochlorobenzene (TNCB). The hypersensitivity was shown to be hapten specific in so far as TNCB did not sensitize for DNFB responses but sensitization with DNFB did allow a marginal response in rats challenged with TNCB. Suppression of the sensitization to DNFB and TNCB could be generated by intravenous injection of dinitrobenzenesulphonic acid (DNBS) or trinitrobenzenesulphonic acid (TNBS), respectively, up to 3 weeks before sensitization. This suppression was hapten specific and could be transferred witb splenic T cells enriched for lymphocytes carrying the OX8 (Tc/s) cell marker. Only the induction phase of sensitization, however, could be suppressed in that way. No suppression acting upon the effector phase could be detected except for a nonspecific local suppression at the site of a previous challenge with an antigen to which the rat was specifically suppressed. This study shows that suppression of contact hypersensitivity in rats is mediated by specific suppressor T cells of which the activation pathway apparently differs from that postulated for mice. Q 1986 Academic k, Inc.