The mucosal immune system of the upper respiratory tract and development of nasal vaccine for upper respiratory tract infection

上呼吸道粘膜免疫系统及上呼吸道感染鼻疫苗的研制

• 批准号: 10307040
• 负责人: MOGI Goro
• 金额: $ 15.04万
• 依托单位: Oita Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307040/
• 关键词: NALT; Intranasal immunization; vaccine; Mucosal immune system; Haemophilus influenzae; Streptococcus pneumoniae; IgA; RS virue; 鼻粘膜; 中耳粘膜; マウス; CD4^+T細胞; P6

A. Experimental Study1. Mucosal immune function of NALTSelected Th2-type cytokine expressing CD4ィイD1+ィエD1 T cells were induced in intranasally-immunized mice NALT. M cells were observed in rat NALT. Antigen-specific IgA antibody titers in nasal wash were increased after immunization of mice without Peyers patches. These findings strongly suggest that NALT functions as an inductive site of nasal IgA response.2. Induction of antigen-specific IgA by intranasal immunization in miceThe greatest antigen-specific IgA response was observed in mice intranasally immunized with P6, an antigen of nontypeable Haemophilus influenzae (NTHi) that is a major pathogen of otitis media. This response was induced not only in the nose but also in the middle ear. In mice immunized intranasally with fimbrial protein of Porhyromonas gingivalis, a causative agent for destructive chronic inflammation in the periodontium, antigen-specific IgA antibodies were induced in nasal mucosae and salivary glands. Thus, int … More ranasal vaccination may be the most effective means for induction of antigen-specific mucosal immune responses in the upper respiratory tract.3. Prevention of virus infection by intranasal immunizationInflammatory reaction was mild in mice with Rs virus injected into the nasal cavity after intranasal immunization with vaccina virus. Nasal administrations of Fab antibodies against RS virus restricted viral proliferation and decreased the inflammatory reaction. These findings also lead us to the conclusion that intranasal immunization is useful for prevention of virus infection in the upper respiratory tract.B. Clinical Study1. The number of P6-specific IgA-secreting cells was greater in the tonsils showing no NTHi than in the samples with the bacteria. The number of P6-specific IgA-secreting cells in tonsils was correlated with IgA antibody titers in nasal secretions. Intratonsillar as well as intranasal immunization with OK-432 increased the number of M-protein-specific antibody-secreting cells in tonsils and antigen-specific antibody activity in nasal secretions. CD4ィイD1+ィエD1 T cells produced Th2-and Th1-type cytokines in response to stimulation with P6 or M-protein. These findings suggest that the palatine tonsils are important as an effector site.2. Adenoid involvement in otitis media with effusion (OME)NTHi was cultured more frequently in adenoids from patients with OME than in patients without OME. A tendency toward increased stratified squamous epithelium was apparent, and reticular epithelium extension was greater in patients with OME. The data suggest that adenoid inflammation is implicated in the pathogenesis of OME.3. Antigen specific-antibody responses in otitis-prone childrenOtitis-prone children exhibited reduced IgGィイD22ィエD2 responses to S. pneumoniae and IgG responses to NTHi. Otitis proneness appears to be related to numerous immunological deficiencies. Less

A.实验研究1.鼻内免疫小鼠NALT诱导表达Th 2型细胞因子的CD 4 + CD 4 + CD 4 + D1 T细胞。在大鼠NALT中观察到M细胞。鼻洗液中的抗原特异性伊加抗体滴度增加免疫后的小鼠无派尔集合淋巴结。这些结果有力地表明NALT作为鼻伊加反应的诱导位点.鼻内免疫小鼠诱导抗原特异性伊加在鼻内免疫小鼠中观察到最大的抗原特异性伊加应答，其中P6是不可分型流感嗜血杆菌（NTHi）的抗原，是中耳炎的主要病原体。这种反应不仅在鼻子中引起，而且在中耳中也引起。牙龈卟啉单胞菌（Porhyromonas gingivalis）的菌毛蛋白经鼻内免疫小鼠，在鼻粘膜和唾液腺中诱导抗原特异性伊加抗体，牙龈卟啉单胞菌是牙周组织中破坏性慢性炎症的病原体。因此，int ...更多信息 鼻腔接种可能是诱导上呼吸道抗原特异性粘膜免疫应答的最有效手段.鼻内免疫预防病毒感染用牛痘病毒鼻内免疫小鼠后，鼻腔内注射Rs病毒，炎症反应轻微。经鼻给予抗RS病毒Fab抗体可抑制病毒增殖并降低炎症反应。这些发现也使我们得出结论，鼻内免疫对于预防上呼吸道病毒感染是有用的。临床研究1. P6特异性IgA分泌细胞的数量在扁桃体中显示没有NTHi比在细菌的样品中更大。扁桃体中P6特异性IgA分泌细胞的数量与鼻分泌物中伊加抗体滴度相关。用OK-432进行扁桃体内和鼻内免疫增加了扁桃体中M蛋白特异性抗体分泌细胞的数量和鼻分泌物中抗原特异性抗体活性。CD 4 + CD 4 + CD 4 + D1+ T细胞在P6或M蛋白刺激下产生Th 2和Th 1型细胞因子。这些发现表明腭扁桃体是重要的效应部位。分泌性中耳炎（OME）腺样体受累的NTHi培养在OME患者的腺样体中比在无OME的患者中更频繁。OME患者的复层鳞状上皮明显增加，网状上皮延伸更大。这些数据表明腺样体炎症与OME的发病机制有关。易患中耳炎的儿童的抗原特异性抗体反应易患中耳炎的儿童对S.肺炎和对NTHi的IgG应答。耳炎倾向似乎与许多免疫缺陷有关。少

项目成果

Imaoka,K.,Kiyono,H.et al: "Nasal immunization of non-human primates with simian immunodeficiency virus p55gag and cholera toxin adjuvant induces Th1/Th2 help for anti-viral immunity." J.Immunol.161. 5952-5958 (1998)

Imaoka,K.,Kiyono,H.等人：“用猿猴免疫缺陷病毒 p55gag 和霍乱毒素佐剂对非人灵长类动物进行鼻腔免疫可诱导 Th1/Th2 有助于抗病毒免疫。”

Kurono Y., Suzuki M., Mogi G., Kiyono H., et al.: "Effcts of intranasal immunization on protective immunity against otitis media"International Journal of Pediatric Otorthinolaryngology. 49(1). 277-229 (1999)

Kurono Y.、Suzuki M.、Mogi G.、Kiyono H.等人：“鼻内免疫对中耳炎保护性免疫的影响”国际儿科耳鼻喉科杂志。

Kurono Y.,et al: "Effects of intranasal immunization on protective immunity against otitis media.Proceedings of the 7th International Congress of Pediatric Otolaryngology." (ed.)Ruben RJ.,Elsevier Science,Amsterdam,The Netherlands,in press.,

Kurono Y.等人：“鼻内免疫对中耳炎保护性免疫力的影响。第七届国际儿科耳鼻喉科大会论文集”。

Kurono Y., Suzuki M., Mogi G., Fujihashi K, McGhee J.R., Kiyono H: "Effects of intranasal immunization on protective immunity against otitis media"Int J Pediatric Otorhinolaryngology. 49 Suppl. 1. 227-229 (1999)

Kurono Y.、Suzuki M.、Mogi G.、Fujihashi K、McGhee J.R.、Kiyono H：“鼻内免疫对中耳炎保护性免疫的影响”Int J 小儿耳鼻喉科。

Yanagita M., Hiroi T., Kitagaki N., Hamada S., Ito H., Shimauchi H., Murakami S., Okada H., Kiyono H.: "Nasopharyngeal-associated lymphoreticular tissue (NALT) immunity: fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bact

Yanagita M.，Hiroi T.，Kitagaki N.，Hamada S.，Ito H.，Shimauchi H.，Murakami S.，Okada H.，Kiyono H.：“鼻咽相关淋巴网状组织（NALT）免疫：菌毛特异性