RESUMO
It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Dermatite de Contato/imunologia , Pele/imunologia , Animais , Antígeno CD11c/genética , Proliferação de Células , Quimiocina CXCL2/biossíntese , Feminino , Memória Imunológica/imunologia , Interleucina-1alfa/farmacologia , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Neutrófilos/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Pele/patologiaRESUMO
BACKGROUND: A better understanding of the means by which topical vitamin D analogues exert their therapeutic effect on psoriasis is of theoretical and practical importance. OBJECTIVE: We sought to clarify whether and how the topical vitamin D analogue calcipotriol (CAL) controls the IL-17A-mediated pathogenesis of murine psoriasis-like dermatitis in vivo. METHODS: Psoriasis-like dermatitis was induced by the topical application of an imiquimod (IMQ)-containing cream on the murine ear for 4 to 6 consecutive days. For topical CAL treatment, mice were treated daily with CAL solution on the ear before IMQ application. RESULTS: Mice treated topically with CAL exhibited much milder IMQ-induced psoriasis-like dermatitis compared with vehicle-treated mice, with impaired accumulation of IL-17A-committed T (T17) cells in the lesional skin. The IMQ-induced upregulation of Il12b and Il23a was marked in the epidermis and was abrogated by CAL application, suggesting CAL-mediated suppression of IL-23 expression. CAL inhibited Il12b and Il23a expression by Langerhans cells ex vivo stimulated with IMQ and CD40 cross-linking. Topical CAL also inhibited T17 cell expansion in the draining lymph nodes of IMQ-treated skin, implying a possible effect on T17 cell-mediated dermatitis at distant sites. In fact, topical CAL application on the IMQ-treated left ear resulted in amelioration of T17 cell accumulation and psoriasis-like dermatitis in the right ear subsequently treated with IMQ. CONCLUSION: Topical CAL can exert its antipsoriatic effect on CAL-treated lesions and, concomitantly, distant lesions by attenuating the T17 cell accumulation in both CAL-treated lesions and draining lymph nodes.
Assuntos
Imiquimode/efeitos adversos , Interleucina-17/imunologia , Psoríase/imunologia , Células Th17/imunologia , Animais , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Imiquimode/farmacologia , Subunidade p40 da Interleucina-12/imunologia , Subunidade p19 da Interleucina-23/imunologia , Camundongos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Psoríase/patologia , Células Th17/patologiaAssuntos
Dermatite/imunologia , Interleucina-17/metabolismo , Psoríase/imunologia , Linfócitos T/imunologia , Tromboxano A2/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Imiquimode , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismoRESUMO
TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.