Murine Allergic Contact Dermatitis Research Articles

Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand.

Blockade of costimulation through the B7-CD28 pathway by CTLA4Ig can lead to Ag-specific T cell tolerance. Most models studied to date involve a Th1-dependent response. To investigate whether the tolerizing effects of CTLA4Ig might vary depending upon the cytokine nature of the immune response, we studied its effects on contact hypersensitivity (CHS) in response to two allergens. In BALB/c mice, both 2,4-dinitrofluorobenzene (DNFB) and FITC induce CHS. However, the DNFB response is Th1-predominant, while the FITC response is Th2 predominant. CTLA4Ig treatment during primary sensitization induced long-lasting unresponsiveness to DNFB, with 88% and 76% inhibition of primary (first challenge) and secondary (re-sensitization and re-challenge) CHS, respectively. In contrast, CTLA4Ig inhibited primary CHS to FITC by over 82% but had little effect on secondary CHS. Consistent with its effects on CHS, the suppressive effect of CTLA4Ig on Th2 cells was short-lived in FITC-sensitized mice, while Th1-like cytokine-secreting cells remained reduced in DNFB-sensitized mice, even when the animals were rechallenged with DNFB. The addition of anti-CD40L Ab to CTLA4Ig was able to induce long-lasting unresponsiveness to FITC, indicating the ability of cells mounting this Th2 response to receive costimulatory signals through either pathway. In conclusion, CHS can be mediated by both Th1 and Th2 cells, and the ability of CTLA4Ig to lead to long-standing nonresponsiveness in this model depends on the nature (i.e., cytokine profile) of the immune response.

RT-PCR Analysis of in Vivo Cytokine Profiles in Murine Allergic Contact Dermatitis to DNCB

To elucidate an in vivo cytokine pattern in allergic contact dermatitis, the mRNAs for IL-2, IL-4, IL-10, IL-12p35, IL-12p40, and IFN-gamma were detected in the skin and spleens of mice with allergic contact dermatitis responses to DNCB using reverse transcription-polymerase chain reaction (RT-PCR). The mRNAs for IL-2, IL-4, IL-10, and IFN-gamma and IL-12 were constitutively expressed in the spleens from control and allergic contact dermatitis mice. Among these cytokines, the mRNAs for IFN-gamma and IL-12p40 were upregulated in mice with allergic contact dermatitis. On the other hand, the mRNAs for IL-2, IL-4, and IFN-gamma were detected only at diseased skin sites of allergic contact dermatitis mice, but not the skin from the control mice. Moreover, both IL-12p35 and IL-12p40 mRNAs were highly expressed in the skin of mice with allergic contact dermatitis responses to DNCB compared with control mice. Therefore, the present study indicates that, in vivo, allergic contact dermatitis mice appear to have a d...

Changes in phenotypically distinct phagocyte subpopulations during nonspecific modulation of contact sensitization.

Environmental influences are increasingly recognized as nonspecific modulators triggering and aggravating allergic diseases. To obtain better insight into the pathomechanisms of these nonantigen-specific phenomena, we studied the augmenting and inhibitory effects of croton oil and glucocorticosteroid (GC) on the induction of murine allergic contact dermatitis. Application of the irritant croton oil simultaneously with the sensitization dose of the contact allergen oxazolone strongly amplified the inflammatory reaction (measured as ear swelling) during the effector phase. Immunohistologically, this effect correlated with an increased percentage of MRP8- and MRP14-positive phagocytes in the infiltrate of the early inflammatory reaction 8 h after sensitization with oxazolone plus croton oil as compared to oxazolone alone (62 vs. 27%; p < 0.05). Intravenously administered GC was used as an inhibitor of contact sensitization. The suppressive effect of GC on sensitization was dependent on the time of its application: suppression of the inflammatory reaction during the effector phase was clearly more pronounced when GC had been injected 1 day as compared to 1 h before sensitization. Correspondingly, the percentage of BM8-positive macrophages in the infiltrate of the early inflammatory reaction 8 h after sensitization was differentially decreased depending on the time of GC application: suppression of the percentage of BM8-positive macrophages was clearly more pronounced when GC had been injected 1 day as compared to 1 h before sensitization (17 vs. 25%; base value without GC 35%; p < 0.05). Furthermore, the percentage of BM8-positive macrophages in the inflammatory infiltrate of the effector phase was increased when sensitization had been enhanced by concomitant irritant contact dermatitis (47 vs. 59%; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Tachykinins and Calcitonin Gene-Related Peptide in Oxazolone-Induced Allergic Contact Dermatitis in Mice

Neuropeptides in primary afferent neurons have been found to be engaged in the immediate type of hypersensitivity. However, their role in the delayed form of hypersensitivity is not yet established. The hypothesis that substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) are involved in delayed hypersensitivity was tested in oxazolone-induced, murine ear allergic contact dermatitis. Concentrations of immunoreactive SP, NKA, and CGRP were measured in extracts of the eczema ears (n = 26), whereas extracts of the opposite ears were used as controls. The SP, NKA, and CGRP contents in the treated ears were on the average 28% (p = 0.001), 32% (p = 0.004), and 15% (p = 0.016), respectively, lower than in the control ears. Lower peptide concentrations in the eczema ears indicate increased release of the peptides because the peptides are rapidly metabolized locally when released and only replenished by axonal transport from the cell bodies. Our results indicate that peptides released from primary afferent neurons play a role in the delayed type of hypersensitivity reactions.

Expression of Intercellular Adhesion Molecule-1 in Murine Allergic Contact Dermatitis

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the interaction of immunocompetent cells in inflammation. It contributes to lymphocyte recruitment, antigen presentation and T-cell activation. Recently, the murine homologue of ICAM-1, originally designated as MALA-2, has been identified. The monoclonal antibody YN1/1.7 for murine ICAM-1 enables the analysis of ICAM-1 expression in murine allergic contact dermatitis, a prototype of cutaneous T-cell-mediated inflammatory response. At 0, 1, 8, 24, 48, 72 h, and 7 and 14 days after challenge with 2,4-dinitrofluoro-1-benzene (DNFB) cryostat sections of ear skin were immunostained for ICAM-1, I-A and mononuclear cells (L3T4, Lyt-2, BM8). In normal skin ICAM-1 labeling was restricted to endothelial cells and dermal dendritic cells/macrophages; keratinocytes (KCs) did not express ICAM-1. The dermal cellular infiltrate increased progressively from 8 to 72 h after DNFB challenge. The majority of infiltrating cells were BM8+ macrophages (75%) and L3T4+ (10%) or Lyt-2+ T cells (10%); maximally 30% of those stained positive for ICAM-1. At 24 h, focal ICAM-1 expression on KCs developed, reached a maximum at 72 h and faded thereafter. Migration of T cells into the epidermal layer started at 48 h at sites which had already expressed ICAM-1. Our data provide evidence that expression of ICAM-1 by epidermal cells precedes infiltration of the epidermis by T lymphocytes as shown before in human cutaneous disorders. Thus, a mouse model may be useful to investigate the role of ICAM-1 in inflammation further.

Studies on the role of leukotrienes in murine allergic and irritant contact dermatitis.

A specific peptidoleukotriene receptor antagonist, Ro 23-3544, was tested for its efficacy in modulating DNFB-induced allergic and croton oil-induced irritant contact dermatitis in mouse ears. Treatment shortly after elicitation of the dermatitis, and for up to 5 days thereafter, was moderately effective in suppressing DNFB-induced ear swelling in a dose-dependent fashion. Daily pre-treatment of the ears for 1 week caused a more marked reduction of DNFB-induced ear swelling during the first 48 h after elicitation. No reduction, but rather an increase in ear swelling was observed with croton oil-induced dermatitis. These results indicate that peptidoleukotrienes play a role in the early stages of elicitation of murine allergic, but not irritant contact dermatitis and that a specific receptor antagonist can only partially reverse the effect of peptidoleukotrienes once the dermatitis is established.

Cyclosporine and Murine Allergic Contact Dermatitis

Cyclosporine is a new antilymphocytic, immunosuppressive agent currently being used primarily in experimental and human organ transplantation. The current study evaluated the effect of systemically administered cyclosporine on a cutaneous T-cell-mediated disorder by using the murine model of allergic contact dermatitis to dinitrofluorobenzene. Cyclosporine was found to significantly inhibit the ear swelling response, whether the drug was given during the early sensitization period or at the time of antigenic challenge to fully sensitized mice. This suppressive effect was reversible when mice were rechallenged with dinitrofluorobenzene 96 hours after the first challenge. Cyclosporine was not effective if given to sensitized animals as late as six hours after challenge. Lastly, the observed inhibition of the ear swelling response to cyclosporine closely paralleled a diminished degree of inflammation seen histopathologically.

Cyclosporine and murine allergic contact dermatitis

Cyclosporine and murine allergic contact dermatitis