Mahapatra Subhashree, Albrecht Melanie, Behrens Barbara, Jirmo Adan, Behrens Georg, Hartwig Christina, Neumann Detlef, Raap Ulrike, Bähre Heike, Herrick Christina, Dittrich Anna-Maria
Department for Pediatric Pneumology, Allergology and Neonatology, Medical School Hannover, Hannover, Germany.
Department of Clinical Immunology and Rheumatology, Medical School Hannover, Hannover, Germany.
PLoS One. 2014 Feb 4;9(2):e87296. doi: 10.1371/journal.pone.0087296. eCollection 2014.
Histamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism.
Establishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation.
In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes.
Use of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism.
Our model demonstrates a role for H1- and H4-receptors in Th2 cell infiltration and cytokine secretion in allergic skin diseases and suggests further studies to evaluate these findings for therapeutic approaches.
组胺引发过敏性皮肤病中的瘙痒，而瘙痒在临床上是极具干扰性的症状。过敏性皮肤病的皮肤病理学受到不同辅助性T细胞亚群的关键影响。然而，不同组胺受体对辅助性T细胞依赖性皮肤病理学的作用尚未得到明确解答。因此，能够专门研究辅助性T细胞亚群和相关介质功能作用的模型，对于深入了解导致过敏性皮肤病的分子途径具有重要价值。它们或许还有助于探索可修正的治疗干预措施，如组胺受体拮抗作用。
通过建立抗原特异性Th细胞的过继转移模型，我们旨在阐明组胺H1和H4受体在Th2依赖性皮肤炎症中的作用。
将体外分化并经卵清蛋白致敏的Th2细胞过继转移到同基因受体小鼠体内。采用特异性组胺H1和H4受体拮抗剂进行体内治疗，以分析这些组胺受体对我们模型中Th2依赖性皮肤病理学的作用。表皮激发后四天的分析包括皮肤组织学、转移的辅助性T细胞的流式细胞术检测以及皮肤引流淋巴结中抗原-细胞因子谱的分析。
使用特异性H1和H4受体拮抗剂揭示了在Th2驱动的皮肤炎症模型中，H1和H4受体对Th2迁移和细胞因子分泌具有关键作用。虽然H1和H4受体拮抗剂均减少了Th2向激发部位的募集，但皮肤引流淋巴结中的局部细胞因子反应仅在联合应用H1和H4受体拮抗剂时才降低，并且肥大细胞计数在H1R、H4R或联合拮抗作用下总体保持不变。
我们的模型证明了H1和H4受体在过敏性皮肤病中Th2细胞浸润和细胞因子分泌中的作用，并建议进一步开展研究以评估这些发现用于治疗方法的可能性。
