Repeated administration of antigen often leads to consequences different from those expected with fewer encounters with the antigen, but little attention has been paid to the effects of repeated epicutaneous application of antigens. To investigate whether repeated epicutaneous application of a contact-sensitizing agent that is generally thought to evoke a typical delayed-type hypersensitivity response could result in adverse or different consequences, BALB/c mice were sensitized with 2,4,6-trinitro-1-chlorobenzine and then were repeatedly elicited on the original sensitized site with the same antigen for 24-48 d. Detailed analyses showed that the time-course of antigen-specific hypersensitivity responses shifted from a delayed-type hypersensitivity to an immediate-type response followed by a late reaction as epicutaneous applications were repeated, a finding different from that previously reported. Development of these hypersensitivity responses was antigen specific, and this shift was associated with epidermal hyperplasia, accumulation of large numbers of mast cells and CD4+ T cells beneath the epidermis, and elevated serum levels of antigen-specific IgE. The immediate-type response to 2,4,6-trinitro-1-chlorobenzine was also induced in 2,4,6-trinitro-1-chlorobenzine-treated, genetically mast cell-deficient W/Wv mice that contained significant numbers of mast cells, but not in similarly treated S1/S1d mice devoid of mast cells. Our experimental system would provide a simple, reproducible animal model for chronic skin inflammation induced by various antigens.

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Psychological factors have long been assumed to be involved in the pathogenesis of allergic skin diseases. The effects of psychological stress on allergic contact dermatitis (ACD) have been experimentally well investigated; however, the effects of ACD on stress responses are largely unknown. Here, we report that preceding chronic ACD dramatically affects the behavioral and physiological stress responses to social isolation (a psychological stressor). In male BALB/c mice, social isolation combined with long-standing (>2 months) ACD by repeated hapten application caused characteristic symptoms, including chronic dermatitis from persistent self-scratching, behavioral changes related to fear/anxiety, and elevated serum IgE levels. The symptoms were maintained by social isolation alone without further hapten application after the onset, and were improved by resocialization. Treatment with topical corticosteroids exacerbated chronic scratch dermatitis, whereas it was effective for chronic ACD. These results show that the symptoms represent a de novo development of a specific disease state and not a mere exacerbation of a preexisting allergic inflammation. With this experimental protocol, similar results were obtained in several other strains of mice. This murine model provides a tool for investigating the pathogenesis and treatment of allergic skin disease with psychodermatological aspects.

We previously demonstrated that repeated application of 2,4,6-trinitro-1-chlorobenzene resulted in a site-restricted shift in the time course of Ag-specific hypersensitivity responses from a typical delayed-type to an early-type response. Here we demonstrated that the cutaneous microenvironment at the time of Ag presentation to T cells in the elicitation, but not the induction, phase of contact hypersensitivity is responsible for the shift. To investigate the differences in the cutaneous cytokine milieu between the acute and chronic phases of contact hypersensitivity, sequential cytokine dynamics after 2,4,6-trinitro-1-chlorobenzene application were assessed in the acute vs chronic lesions. In the acute lesions, increased mRNA levels for IFN-gamma and IL-2 were rapidly detected at 1 h and remained elevated at 12 h, while mRNA expression for IL-4 and IL-10 was minimally up-regulated between approximately 12 and 24 h. In chronic lesions, high levels of constitutive expression of IL-4 mRNA were observed and IL-10 mRNA was dramatically up-regulated at 1 approximately 3 h in an Ag-specific fashion, whereas the expression of Th1-type cytokines was markedly reduced. Increased mRNA levels for Th2-type cytokines in the chronic lesions was also reflected at the protein level. These results indicate that repeated elicitation with Ag alters the balance of cytokines released locally, with a shift toward Th2-dominated responses, which would represent the natural evolution processes directed toward reducing a more deleterious Th1 response.