Tozuka Miyuki, Oka Tatsuya, Jounai Nao, Egawa Gyohei, Ishii Ken J, Kabashima Kenji, Takeshita Fumihiko
Kitasato Daiichi Sankyo Vaccine Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Syogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan.
J Dermatol Sci. 2016 Apr;82(1):38-45. doi: 10.1016/j.jdermsci.2015.11.008. Epub 2015 Nov 22.
It has been clinically demonstrated that intradermal (ID) vaccines have a potential to confer a superior immunogenic profile compared to intramuscular (IM) or subcutaneous (SC) vaccines. In terms of distribution of a vaccine antigen depending on the administration routes, at least two independent immunogenic pathways of the vaccines have been proposed: (1) the antigen recognition by the immune cells present at the vaccine-administered site and (2) the antigen recognition by the lymph node (LN)-resident immune cells through the lymphatic flow from the vaccine-administered site after the antigen is directly delivered into the draining LNs.
In order to clarify the key components for the immunogenic pathway of the ID vaccine, the correlation between the kinetics of the antigen distribution to the draining LNs and antibody responses to the antigen were evaluated.
We compared the antibody responses in the groups with by surgical removal of the administration site immediately after the ID administration, and by surgical removal of the draining LNs before the ID administration.
The results suggested that the efficient and direct antigen delivery to the draining LNs plays an important role in the antibody responses to the ID vaccine. Indeed, it was confirmed that the direct administration into the draining LNs with the antigen elicited comparable levels of the antibody responses with the ID vaccine. At the cellular level, it was shown that the LN-resident immune cells such as B cells, dendritic cells, and macrophages including medullary macrophages and subcapsular sinus macrophages interacting with the antigens following the ID administration. Finally, we demonstrated by immunofluorescence analysis that the lymphatic vessels are more diffusely distributed in the dermis as compared with the subcutaneous area and muscle.
The results of the present study suggested that the skin is an optimal tissue to facilitate the vaccine antigen access to the draining LNs, which is an important immunogenic pathway of the ID vaccine. Further elucidation of regulatory mechanisms underlying such an immunogenic pathway of the ID vaccine would provide us with elements for the development of novel adjuvants and devices to enhance the immunogenicity of the ID vaccines.
临床研究表明，与肌内注射（IM）或皮下注射（SC）疫苗相比，皮内注射（ID）疫苗具有产生更优免疫原性的潜力。就疫苗抗原根据给药途径的分布而言，已提出疫苗至少有两条独立的免疫原性途径：（1）疫苗给药部位存在的免疫细胞对抗原的识别；（2）抗原直接输送到引流淋巴结后，淋巴结（LN）驻留免疫细胞通过从疫苗给药部位的淋巴流动对抗原的识别。
为阐明ID疫苗免疫原性途径的关键组成部分，评估了抗原向引流淋巴结分布的动力学与对抗原的抗体反应之间的相关性。
我们比较了ID给药后立即手术切除给药部位的组以及ID给药前手术切除引流淋巴结的组中的抗体反应。
结果表明，向引流淋巴结高效、直接地递送抗原在对ID疫苗的抗体反应中起重要作用。事实上，已证实将抗原直接注射到引流淋巴结中引发的抗体反应水平与ID疫苗相当。在细胞水平上，结果表明，ID给药后，LN驻留免疫细胞如B细胞、树突状细胞以及包括髓质巨噬细胞和被膜下窦巨噬细胞在内的巨噬细胞与抗原相互作用。最后，我们通过免疫荧光分析证明，与皮下区域和肌肉相比，淋巴管在真皮中的分布更为广泛。
本研究结果表明，皮肤是促进疫苗抗原进入引流淋巴结的最佳组织，而引流淋巴结是ID疫苗重要的免疫原性途径。进一步阐明ID疫苗这种免疫原性途径的调控机制将为我们提供开发新型佐剂和装置以增强ID疫苗免疫原性的要素。
