Intradermal Delivery of Antigens Enhances Specific IgG and Diminishes IgE Production: Potential Use for Vaccination and Allergy Immunotherapy

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.

皮肤依靠坚韧且柔韧的多层屏障获得保护，同时作为机体抵御入侵颗粒的免疫应答第一道防线。多年以来，皮肤一直是接种特定疫苗以预防传染病的常用组织，但目前学界对皮肤免疫应答的具体机制仍未完全明晰。本研究采用细小型注射针头，将卵清蛋白（OVA）精准注射至小鼠皮肤的限定区域，即皮内注射（intradermal, ID），并与皮下注射（subcutaneous, SC）及经皮贴片给药OVA的组别对比抗体应答情况。经皮贴片给药可诱导针对OVA的高IgE应答，但IgG生成水平较低；皮内注射与皮下注射均可诱导高水平IgG生成，且皮内注射无需任何佐剂即可实现更高的IgG产量。此外，皮内注射可抑制卵清蛋白特异性IgE的生成。研究发现，皮内注射能够有效激活皮肤驻留树突状细胞（dendritic cells, DCs），营造Th1偏态免疫环境并抑制IgE生成。皮内注射的免疫应答受朗格阳性真皮树突状细胞调控：OVA主要由这类细胞摄取，当瞬时清除这些细胞后，IgE应答的抑制效应消失，且IgG1生成水平升高。我们还通过尝试抑制实验诱导血清高IgE水平小鼠的持续性IgE生成，验证了皮内注射是否可作为有效的过敏治疗手段。结果显示，多次皮内注射OVA可阻止反复过敏原激发后血清OVA特异性IgE的升高；相比之下，皮下注射OVA仅能短暂抑制卵清蛋白特异性IgE的生成。上述研究结果表明，皮内注射可更高效地诱导抗原特异性IgG生成，因此有望在佐剂含量极低甚至无需佐剂的情况下用于疫苗递送。此外，皮内注射可抑制IgE生成并诱导Th1偏态免疫应答，提示该给药途径或可应用于过敏免疫治疗。