Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, Pa.
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, Pa; Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pa; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pa.
J Allergy Clin Immunol. 2022 Jul;150(1):114-130. doi: 10.1016/j.jaci.2021.12.794. Epub 2022 Jan 24.
Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated.
We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA).
In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD.
We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner.
Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.
变应性接触性皮炎（CD）是一种由 1 型适应性免疫引起的慢性炎症性皮肤病，目前对其抗原（Ag）特异性免疫疗法存在未满足的需求。接触敏化剂会刺激促炎神经肽物质 P 和血激肽 1 的分泌，这些物质通过神经激肽-1 受体（NK1R）信号传递，促进 CD 的固有和适应性免疫反应。因此，缺乏 NK1R 的小鼠会出现 CD 受损。尽管如此，针对 NK1R 靶向治疗 CD 的作用和治疗机会仍有待阐明。
我们试图通过将半抗原和 NK1R 拮抗剂皮肤共递送至可溶性微针阵列（MNA）中，开发一种针对 Ag 的免疫抑制方法来治疗 CD。
使用接触超敏反应的体内小鼠模型和人类皮肤的体外模型来描述 NK1R 信号在 CD 中的作用和机制，以及接触敏化剂 NK1R 拮抗剂 MNA 的免疫抑制作用。
我们在小鼠中证明 CD 需要 NK1R 信号通过物质 P 和血激肽 1。角质形成细胞和树突状细胞中特异性缺失 NK1R，但肥大细胞中不缺失 NK1R，可预防 CD。皮肤共递送半抗原或 Ag MNA 可抑制小鼠和人类皮肤中神经肽介导的皮肤炎症，促进 Ag 特异性效应 T 细胞的删除，并增加调节性 T 细胞，从而以 Ag 特异性方式局部和全身预防 CD 的发作和复发。
通过工程化局部皮肤神经免疫网络进行免疫调节可用于治疗 CD 等由 1 型免疫引起的皮肤病。
