ABSTRACT
BACKGROUND: Toll-like receptor (TLR) 4 is a critical receptor and signal transducer for lipopolysaccharide (LPS), a major component of Gram-negative bacteria. The MyD88-independent pathway downstream of TLR4 leads to functional dendritic cell (DC) maturation, although LPS-induced cytokine production from DCs is MyD88-dependent. OBJECTIVES: We investigated whether intracutaneously injected LPS alters the functions of cutaneous DCs, leading to enhanced contact hypersensitivity (CH). METHODS: The ear swelling response was measured to evaluate the magnitude of CH. Cell proliferation of allogeneic splenocytes stimulated by DC-enriched draining lymph node (LN) cells was measured by performing a [(3)H]-thymidine incorporation assay. Epidermal I-A+ cells were evaluated under an epifluorescent microscope. I-A+ FITC-bearing cells from the draining LNs 24h after FITC application were analyzed on FACScan. RESULTS: LPS augmented CH induction in C3H/HeN (HeN) and MyD88-knockout (KO) mice but not in C3H/HeJ (HeJ) and H-2S(d)-bearing strains such as BALB/c mice. LPS failed to augment the allo-stimulatory ability of DCs in the draining LNs after hapten applications. LPS altered the density and morphology of epidermal I-A+ cell in HeN and BALB/c mice but not in TLR4-deficient HeJ mice. LPS increased the proportion of I-A+ FITC-bearing cells in the LNs 24h after FITC application in HeN, but not in BALB/c and HeJ. CONCLUSIONS: LPS augments the ability of DCs to migrate to the draining LNs, leading to enhanced CH via a TLR4-dependent, MyD88-independent pathway. The different effects of LPS on CH in some strains of mice may explain individual differences in the susceptibility to establish CH to daily antigen exposures in clinical settings.
Subject(s)
Dendritic Cells/immunology , Dermatitis, Contact/immunology , Lipopolysaccharides/immunology , Toll-Like Receptor 4/metabolism , Animals , Cells, Cultured , Chemotaxis , Dinitrofluorobenzene , Disease Models, Animal , H-2 Antigens/metabolism , Haptens , Injections, Intradermal , Langerhans Cells/immunology , Lipopolysaccharides/administration & dosage , Lymph Nodes/immunology , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/deficiency , Myeloid Differentiation Factor 88/genetics , Species Specificity , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
BACKGROUND: Antihistamines are widely used for the treatment of allergic diseases, such as urticaria and allergic rhinitis. They are also effective for the treatment of diseases in which T cells are mainly involved in the pathogenesis, such as atopic dermatitis (AD) and contact dermatitis. Dendritic cells (DCs) drive polarization of naive T cells into Th1 or Th2 subsets, and are also likely to be involved in AD pathogenesis. OBJECTIVES: The aim of this study was to determine the effects of antihistamines on DCs and CD4+ T cells. METHODS: Human monocyte-derived DCs (MoDCs) and autologous CD4+ T cells were obtained from healthy subjects, and cultured together or independently in the presence of antihistamines. As a stimulant, we used staphylococcal enterotoxin B or the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD28 mAb. The concentrations of cytokines and chemokines in culture supernatants were measured by ELISA. The expression of surface molecules on MoDCs was measured by flow cytometry. Cell proliferation in the cocultures of MoDCs and CD4+ T cells (DC-T cocultures) was measured by a [(3)H] thymidine incorporation assay. RESULTS: Antihistamines inhibited the production of IFN-gamma, and enhanced the production of IL-4 in DC-T cocultures. Antihistamines inhibited the production of TNF-alpha, TARC, MDC, IP-10, and Mig from MoDCs. Epinastine, one of antihistamines, suppressed the expression of ICAM-1 (CD54) on MoDCs. Epinastine also inhibited the proliferation of CD4+ T cells cocultured with MoDCs. CONCLUSIONS: Our findings show that antihistamines regulate immune responses by affecting the interaction between DCs and CD4+ T cells, and further DCs and CD4+ T cells independently, which may partially contribute to the control of allergic diseases such as AD and contact dermatitis.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Enterotoxins/immunology , Histamine H1 Antagonists/pharmacology , Interferon-gamma/immunology , Interleukin-4/immunology , ADAM Proteins/antagonists & inhibitors , ADAM Proteins/biosynthesis , ADAM Proteins/immunology , Adult , Antibodies, Monoclonal/immunology , CD28 Antigens/immunology , CD28 Antigens/metabolism , CD3 Complex/immunology , CD3 Complex/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation/drug effects , Chemokine CCL17/biosynthesis , Chemokine CXCL10/biosynthesis , Chemokine CXCL9/biosynthesis , Coculture Techniques , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Humans , Intercellular Adhesion Molecule-1/immunology , Interferon-gamma/biosynthesis , Interleukin-4/biosynthesis , Middle Aged , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/immunologyABSTRACT
BACKGROUND: The relationship between herpesvirus reactivation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) is unclear. OBJECTIVE: We sought to examine the relationship between human herpesvirus (HHV) reactivation and rash/GVHD after allo-SCT by prospective evaluation. METHODS: Fifteen patients who had received allo-SCT underwent prospective serial examinations for human herpesvirus 6 (HHV-6), HHV-7, cytomegalovirus, and Epstein-Barr virus DNA in the blood by polymerase chain reaction and real-time polymerase chain reaction. Serum interferon gamma, interleukins 4 and 10, tumor necrosis factor alpha, and soluble interleukin 2 receptor (sIL-2R) were also measured. RESULTS: In 10 of 15 patients, macular/papular eruptions were seen after allo-SCT and GVHD was diagnosed. In 8 patients with rash, HHV-6 DNA levels correlated with the cutaneous manifestation. Interleukin 10 and sIL-2R also increased in association with rash. LIMITATIONS: The number of patients in our study was relatively small. Not all patients were examined for cytokines and sIL-2R. CONCLUSIONS: HHV-6 reactivation may be involved in the pathogenesis of rash/GVHD after allo-SCT.
