IL-12 Reverses Established Antigen-Specific Tolerance of Contact Sensitivity by Affecting Costimulatory Molecules B7-1 (CD80) and B7-2 (CD86) (original) (raw)
Related papers
Pharmacological Reports, 2012
Background: Allergic contact dermatitis (ACD) is a common clinical condition in industrialized countries and often causes occupational diseases. Animal model of contact sensitivity (CS) is commonly used to study ACD in mice and can be induced by skin application of haptens. It has been previously shown that CS is mediated by CD4 + or CD8 + T effector cells. More recently it was found that also liver NK cells can play a role of CS effector cells in mice. Methods: The aim of the present study was to test whether skin-induced suppression could inhibit CS response in vivo. Results: Here we show that EC immunization of normal mice with hapten conjugated protein antigen prior to hapten sensitization suppresses Th1, Tc1 and NK mediated CS responses. Conclusions: These data strongly suggest that maneuver of EC immunization may have important implications for designing therapeutic schemes aimed at modulating unwanted immune responses in contact hypersensitivity.
Interleukin-12 Enhances Contact Hypersensitivity by Modulating the In Vivo Cytokine Pattern in Mice
Journal of Interferon & Cytokine Research, 1998
It has been proven that interleukin-12 (11-12) can modify Thl and Th2 cell-mediated immune diseases by altering the development and cytokine production of the cells. In this study, we investigated the in vivo immunomodulatory effect of recombinant murine IL-12 on contact hypersensitivity, a Thl cell-mediated disease. For this purpose, Balb/C mice were sensitized with 3% 4-ethyoxymethylene-2-phenyl-oxazol-5-one (OXAZ), and recombinant mouse IL-12 was given simultaneously during the induction phase. Contact allergy was then elicited by ear challenge with 1 % OXAZ. We examined the mouse ear swelling response, in vivo cytokine gene expression in the skin and local lymph nodes, and in vitro cytokine production by the spleen lymphocytes. It was found that in vivo IL-12 treatment during the induction phase significantly enhanced the ear swelling response to OXAZ in sensitized mice. Moreover, remarkable mononuclear cell infiltration and edema and higher expression of Thl cytokine mRNAs (IL-2 and interferon-y) in the skin lesion and local lymph nodes were observed in contact allergic mice with IL-12 treatment compared with contact allergic mice without IL-12 treatment. The expression of Th2 cytokine mRNA (IL-4) in the skin lesion and local lymph nodes, however, was largely downregulated, with no change in IL-5 mRNA in IL-12-treated contact allergic mice. We found, unexpectedly, that, similar to the effects on phytohemagglutinin (PHA) stimulated in vitro IL-2 and IFN-y production, PHA-induced in vitro IL-4 production was enhanced in the spleen lymphocytes from IL-12-treated contact allergic mice. Our results indicate that exogenous IL-12 enhanced contact hypersensitivity probably because of the in vivo promoting and suppressing effects of IL-12 on Thl and Th2 gene expression, respectively.
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.
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.
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
Essential Role of CCR6 in Directing Activated T Cells to the Skin during Contact Hypersensitivity
Journal of Investigative Dermatology, 2008
CCR6 is expressed in a number of dermatological inflammatory diseases. Here, we report that mice sensitized with the hapten oxazolone had increased numbers of CCR6 þ T cells in the draining lymph nodes. Using CCR6 À/À mice, we assessed the role of CCR6 on the development of contact hypersensitivity. After hapten sensitization and re-challenge, ear swelling in CCR6 À/À animals was reduced 80% as compared with wild-type (WT) control mice. This decreased level of inflammation was not related to an inhibition in T-cell activation, because CCR6 À/À lymph node cells from sensitized mice produced threefold higher levels of IFN-g in culture than cells from sensitized WT mice and, when these cells were directly injected into the site of hapten challenge, induced a robust inflammatory response. However, intravenous injection of CCR6 À/À lymph node cells from sensitized mice were unable to prime naive mice to re-challenge whereas cells from primed WT mice were able to sensitize animals. These results suggest that CCR6 plays an important role in directing the trafficking of activated T cells into the skin and suggests that a CCR6 antagonist could be useful to treat skinmediated inflammatory reactions.
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...
Australasian Journal of Dermatology, 1989
Interleukin-l (II^l) is the central hormone of acute inflammation. Previous studies have demonstrated that an Interleukin-l inhibitor (ILS) derived from human gingival epithelial cell cultures abrogates the effect of IL-1 on human Langerhans cells and murine thymocytes in vitro. The present study investigated the effect of ILS on the induction and elicitation of contact hypersensitivity (CHS) to 2,4-dinitro-l-fluorobenzene (DNFB). Systemic administration of ILS 6 days prior to sensitisation significantly blocked the induction of CHS to DNFB in Balb/c mice. In addition, i.v. injection of ILS 24 or 48 hours prior to the elicitation of CHS produced a reduction in ear swelling, but the suppressive effect was less profound than when ILS was administered prior to sensitisation. Thus, ILS production by epithelial cells is a possible mechanism for the down-regulation of cutaneous immune responses.