transforming-growth-factor-beta and Dermatitis--Allergic-Contact

Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the development of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-beta. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively.

Topics: Allergens; Animals; Cytokines; Dermatitis, Allergic Contact; Desensitization, Immunologic; Haptens; Humans; Immune Tolerance; Immunosuppression Therapy; Interleukin-10; Interleukin-2; Models, Animal; Models, Biological; PUVA Therapy; T-Lymphocyte Subsets; Transforming Growth Factor beta

The anti-allergic mechanism of heat-killed Lactobacillus acidophilus strain L-92 has not been fully investigated. Recent studies have reported that CD4(+)CD25(+)Foxp3(+) (forkhead box P3) T regulatory (Treg) cells play important roles in controlling allergic diseases. Hence, we examined the effect of orally administered L-92 on CD4(+)CD25(+)Foxp3(+) cell populations. BALB/c mice were supplemented daily with L-92 by gavage for 5 weeks. 2,4-Dinitrofluorobenzene (DNFB) was used to induce allergic contact dermatitis (ACD) in mice. Fluorescent-activated cell sorter (FACS) analysis was used to determine CD4(+)CD25(+)Foxp3(+) T cell populations in spleen and cervical lymph nodes (CLN). Interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and Foxp3 mRNA expressions in mouse ear skin were investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of CD4(+)CD25(+)Foxp3(+) T cell populations were significantly increased in both spleen and CLN of L-92-fed group than vehicle and control. In addition, L-92 produced higher levels of Foxp3, IL-10 and TGF-β compared to control mice. These results suggest that L-92 can up-regulate the number of Treg cells to suppress the progression of DNFB-induced contact dermatitis in mice.

Topics: Animals; CD4 Antigens; Dermatitis, Allergic Contact; Female; Forkhead Transcription Factors; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lactobacillus acidophilus; Mice; Mice, Inbred BALB C; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Genes involved in the inflammatory response resulting in allergic contact dermatitis (ACD) are only partly known. In this study, we introduce the use of high-density oligonucleotide arrays for gene expression profiling in human skin during the elicitation of ACD. Skin biopsies from normal and nickel-exposed skin were obtained from seven nickel-allergic patients and five nonallergic controls at four different time points during elicitation of eczema. Each gene expression profile was analyzed by hybridization to high-density oligonucleotide arrays. Cluster analysis of 74 genes found to be differentially expressed in the patients over time revealed that the patient samples may be categorized into two groups: an early time-point group (no clinical reaction) and a late time-point group (clinical reaction). Bioinformatics analyses unraveled the potential involvement of signal transducers and activator of transcription and small/mothers against decepentaplegic (SMAD) transcription factors in the late time-point gene expression patterns. Concerning specific genes, the homeostatic chemokine CCL19 was unexpectedly found to be highly expressed in cells scattered in the deep dermis of the late time-point samples. Taken together, these findings suggest hitherto unknown roles of SMAD transcription factors and of CCL19 in the elicitation phase of ACD.

Topics: Adult; Biopsy; Chemokine CCL19; Chemokines, CC; Cluster Analysis; Dermatitis, Allergic Contact; Down-Regulation; Female; Gene Expression Profiling; Humans; Middle Aged; Multivariate Analysis; Oligonucleotide Array Sequence Analysis; Skin; Smad Proteins; Transcription Factors; Transforming Growth Factor beta; Up-Regulation

Human monocyte-derived dendritic cells (MoDCs) obtained from peripheral blood monocytes (PBMC) cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) can be activated in vitro by a variety of simple chemicals such as haptens and several metals. Recently, it has been demonstrated that transforming growth factor-beta1 (TGF-beta1) can induce further differentiation of MoDCs to the cells that share some characteristics with epidermal Langerhans cells, i.e. they contain Birbeck granules and express E-cadherin. In this study, using such TGF-beta1-treated dendritic cells (TGF-beta1+ DCs), we examined the in vitro effects of representative haptens, i.e. NiCl2 and dinitrochlorobenzene (DNCB), on their phenotypic and functional characteristics, comparing with those reported in vivo in epidermal Langerhans cells during the sensitization phase of a contact sensitivity reaction. Treatment of TGF-beta1+ DCs with NiCl2 increased their expression of the molecules related to antigen presentation such as CD86, major histocompatibility complex class I and class II, and CD83, although weakly, in addition to that of those essential for their migration to the regional lymph nodes, such as CD49e, CD44 and its variant 6, while it down-regulated the expression of the molecules required for homing to the skin and staying in the epidermis, such as cutaneous leucocyte antigen (CLA) and E-cadherin. It also increased the production of tumour necrosis factor-alpha, but not that of IL-1beta or IL-12. DNCB also increased their CD86 expression and down-regulated E-cadherin and CLA, but did not affect other phenotypic changes that were observed in TGF-beta1+ DCs treated with NiCl2. TGF-beta1+ DCs treated with either NiCl2 or DNCB increased their allogeneic T-cell stimulatory function. In addition, reverse transcribed polymerase chain reaction revealed augmented expression of chemokine receptor 7 mRNA by TGF-beta1+ DCs when treated with either NiCl2 or DNCB. Moreover, consistent with this data, TGF-beta1+ DCs treated with these chemicals chemotactically responded to macrophage inflammatory protein-3beta. These data suggest the possibility that TGF-beta1+ DCs present a good in vitro model to study the biology of epidermal Langerhans cells.

Topics: Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Cadherins; Cell Culture Techniques; Chemokine CCL19; Chemokines, CC; Cytokines; Dendritic Cells; Dermatitis, Allergic Contact; Haptens; Humans; Immunophenotyping; Langerhans Cells; Lipopolysaccharide Receptors; Lymphocyte Activation; Matrix Metalloproteinase 9; Membrane Glycoproteins; Receptors, CCR7; Receptors, Chemokine; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

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.

Topics: Administration, Cutaneous; Allergens; Animals; Cytokines; Dermatitis, Allergic Contact; Drug Administration Schedule; Ear; Granulocyte-Macrophage Colony-Stimulating Factor; Interferon-gamma; Interleukins; Male; Mice; Mice, Inbred BALB C; Picryl Chloride; Polymerase Chain Reaction; RNA, Messenger; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The mechanisms underlying the induction of immunological tolerance after feeding soluble exogenous antigens, including proteins and haptens, are still unclear. Using a model of oral tolerance to the contact-sensitizing hapten 2,4-dinitrochlorobenzene (DNCB), we have compared the ability-of intestinal epithelial cells and of Peyer's patch APC to present DNCB in vitro or ex vivo after oral feeding, to specific peripheral lymph node T cells from DNCB-sensitized mice. In contrast to Peyer's patch APC, which induce efficient hapten-specific T cell activation upon exposure to the hapten either in vitro or in vivo, mature MHC class-II-positive intestinal epithelial cells were unable to induce T cell activation in either case. Interestingly, enterocytes from DNCB-fed mice exerted a dramatic inhibitory effect on the proliferative response of hapten-primed T cells in response to dinitrobenzene sulfonate presented by syngeneic spleen cells. This inhibitory effect, which was also observed with supernatant of intestinal epithelial cells from DNCB-fed mice, could be reversed by neutralizing anti-transforming growth factor (TGF)-beta antibodies. In addition, pre-incubation of hapten-sensitized T cells with enterocytes from DNCB-fed mice induced T cell anergy, which could be reversed by exogenous interleukin-2 or interleukin-4. These data demonstrate that intestinal epithelial cells activated in vivo by oral administration of DNCB are able to block proliferation of activated T cells through secretion of immunosuppressive cytokines such as TGF-beta. It is proposed that intestinal epithelial cells may play a significant role in oral tolerance by limiting T cell-mediated hypersensitivity responses.

Topics: Administration, Oral; Animals; Antigen-Presenting Cells; Culture Media, Conditioned; Dermatitis, Allergic Contact; Dinitrochlorobenzene; Dinitrofluorobenzene; Epithelial Cells; Female; Haptens; Histocompatibility Antigens Class II; Immune Tolerance; Immunization; Interleukin-2; Interleukin-4; Intestinal Absorption; Intestinal Mucosa; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred C3H; Peyer's Patches; Spleen; T-Lymphocyte Subsets; Transforming Growth Factor beta