Repeated elicitation of contact hypersensitivity induces a shift in cutaneous cytokine milieu from a T helper cell type 1 to a T helper cell type 2 profile.

Abstract

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.

Pharmacological Profile of Difamilast, a Novel Selective Phosphodiesterase 4 Inhibitor, for Topical Treatment of Atopic Dermatitis

“…Various animal models have been established to study AD pathogenesis, and one such widely used model is the mouse model of chronic allergic contact dermatitis induced by repeated hapten application. Kitagaki et al (1995Kitagaki et al ( , 1997 reported that in this model, the skin lesions show findings similar to the reported clinical manifestations, such as edema; epidermal hyperplasia; CD4 + cell, granulocyte, and mast cell infiltration; and dominant T helper 2 cell cytokine expression.…”

Establishment and Characterization of Mild Atopic Dermatitis in the DNCB-Induced Mouse Model

“…Our literature search shows that this classification is difficult for hlAD murine skin. Chen et al [55] reports that TH2 cytokines are more prominent in disease stages while Kitagaki et al [56] shows that a prolonged antigen treatment leads to a shift from a TH1 to a TH2 cytokine response and a study on Stat6VT mice reveals a simultaneous increase in IL-4 and IFN-γ mRNA expression from the acute to chronic phase [57]. Since data are limited, an explicit assignment to an acute or chronic stage of the DNCB-treated skin lesions, as it is described for human AD, is not yet possible in this model.…”

Assessment of Comorbidities Associated With Allergic Contact Dermatitis in the United States: A Retrospective Claims-Based Study

“…Elevations of proinflammatory cytokines have also been noted in cardiovascular disease and act by increasing insulin resistance or oxidizing low density lipoproteins, thus denoting a common disease etiopathogenesis 6,23 . In addition, it has been suggested that chronic ACD may shift the cytokine balance from a T helper (Th)1 to a T H 2-mediated process; thus, chronic ACD could potentially be associated with similar comorbidities to other diagnoses that share overactivation of the T H 2 axis, such as AD 24 . Furthermore, gene expression and cellular studies have demonstrated that ACD immunopathogenesis is mediated by T H 1, T H 17, and T H 2 pathways in an allergen-dependent manner; the T H 17 pathway has been correspondingly implicated in the pathogenesis of cardiovascular diseases in both in vivo and clinical studies 22,25,26 …”

“…6,23 In addition, it has been suggested that chronic ACD may shift the cytokine balance from a T helper (Th)1 to a T H 2-mediated process; thus, chronic ACD could potentially be associated with similar comorbidities to other diagnoses that share overactivation of the T H 2 axis, such as AD. 24 Furthermore, gene expression and cellular studies have demonstrated that ACD immunopathogenesis is mediated by T H 1, T H 17, and T H 2 pathways in an allergen-dependent manner; the T H 17 pathway has been correspondingly implicated in the pathogenesis of cardiovascular diseases in both in vivo and clinical studies. 22,25,26 ACD was significantly associated with obesity, hypertension, and hyperlipidemia.…”