Yasuda Takuwa, Ura Takehiro, Taniguchi Masaru, Yoshida Hisahiro
Laboratory for Immunogenetics, RIKEN Research Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan.
Hospital Company R&D Department, Terumo Corporation, Kanagawa, Japan.
PLoS One. 2016 Dec 14;11(12):e0167952. doi: 10.1371/journal.pone.0167952. eCollection 2016.
Skin is protected by a tough but flexible multilayered barrier and is a front line for immune responses against invading particles. For many years now, skin has been a tissue where certain vaccines are injected for the prevention of infectious disease, however, the detailed mechanisms of the skin immune response are not yet well understood. Using thin and small injection needles, we carefully injected OVA into a restricted region of mouse skin, i.e., intradermal (ID), and examined the antibody response in comparison with subcutaneous (SC) injection or epicutaneous patch administration of OVA. Epicutaneous patches induced a high IgE response against OVA, but IgG production was low. High IgG production was induced by both ID and SC injection, moreover, ID injection induced higher IgG production without any adjutants. Furthermore, OVA-specific IgE production was diminished by ID injection. We found that ID injection could efficiently stimulate skin resident DCs, drive Th1-biased conditions and diminish IgE production. The ID injection response was regulated by Langerin+ dermal DCs, because OVA was taken up mainly by these cells and, after transiently deleting them, the IgE response was no longer diminished and IgG1 production was enhanced. We also tested whether ID injection might be an effective allergy treatment by attempting to inhibit ongoing IgE production in mice with experimentally induced high serum IgE levels. Multiple ID injections of OVA were shown to prevent elevation of serum OVA-specific IgE after repeated allergen challenge. In contrast, SC OVA injection could only transiently inhibit the OVA-specific IgE production. These findings indicated that ID injection results in higher induction of antigen-specific IgG, and thus may be useful for vaccine delivery with little or no adjuvant components. Moreover, the observed diminishment of IgE and induction of Th1-biased immune responses suggest that ID may be a useful injection route for allergy immunotherapy.
皮肤由一层坚韧但富有弹性的多层屏障保护，是抵御入侵颗粒的免疫反应的前沿阵地。多年来，皮肤一直是注射某些疫苗以预防传染病的组织，然而，皮肤免疫反应的详细机制尚未得到充分了解。我们使用细小的注射针，将卵清蛋白（OVA）小心地注射到小鼠皮肤的一个受限区域，即皮内（ID），并与皮下（SC）注射或OVA的表皮贴片给药相比，检测抗体反应。表皮贴片诱导了针对OVA的高IgE反应，但IgG产生量较低。ID和SC注射均诱导了高IgG产生，此外，ID注射在没有任何佐剂的情况下诱导了更高的IgG产生。此外，ID注射使OVA特异性IgE产生减少。我们发现ID注射可以有效刺激皮肤驻留树突状细胞（DCs），驱动Th1偏向的状态并减少IgE产生。ID注射反应受朗格汉斯蛋白阳性真皮DCs调节，因为OVA主要被这些细胞摄取，在短暂清除它们后，IgE反应不再减弱，IgG1产生增强。我们还通过尝试抑制实验诱导的高血清IgE水平小鼠中正在进行的IgE产生，来测试ID注射是否可能是一种有效的过敏治疗方法。多次ID注射OVA被证明可以防止反复过敏原攻击后血清OVA特异性IgE升高。相比之下，SC注射OVA只能短暂抑制OVA特异性IgE产生。这些发现表明，ID注射导致更高的抗原特异性IgG诱导，因此可能有助于在几乎没有或没有佐剂成分的情况下进行疫苗递送。此外，观察到的IgE减少和Th1偏向免疫反应的诱导表明，ID可能是过敏免疫治疗的一种有用注射途径。
