Inhibition of allergic and autoimmune responses by means of food proteins and peptides.

通过食物蛋白质和肽抑制过敏和自身免疫反应。

• 批准号: 07406006
• 负责人: KAMINOGAWA Shuichi
• 金额: $ 16万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07406006/
• 关键词: Allergy; Autoimmune disease; Oral tolerance; Altered peptide ligand; beta-Lactoglobulin; alpha_<s1>-Casein; Ovalbumin; Collagen; アナログペプチド; T細胞; トランスジェニックマウス; 抗体産生; サイトカイン産生; α_<S1>-カゼイン; 免疫抑制; 消化耐性; II型コラーゲン; T細胞抗原決定基; MHCクラスII分子

Increase in the number of patients with allergies or autoimmune diseases have aroused the demand for developing safe and efficient means of treatment for these diseases. We aimed to develop such treatment by means of food proteins and peptides, and their amino-acid substituted analogs. 1.T-and B-cell responses to food allergens or a homologue of a self-antigen were analyzed in mice and in patients allergic to cow's milk. 2.Antigenic structure of beta-lactoglobulin, a major milk allergen, was analyzed in detail. Single amino-acid substituted analogs of beta-lactoglobulin or its partial peptide were examined for their inhibitory effect on allergen-specific immune responses, and shown to be effective. Moreover, we showed that single substituted analogs of a peptide from alpha_<s1>-casein, another major milk allergen, could modulate the CD8^+T-cell responses to the allergen. 3.The condition required for and the mechanism of induction of oral tolerance was investigated. We clarified the roles of CD4^+T cells, CD8^+T cells, and B cells, and the relationship between the dose of orally administered antigen and the induction of oral tolerance. Furthermore, the immune responses to orally administered antigens, including those of the gut-associated lymphoid tissue, were analyzed using T-cell receptor transgenic mice. 4.A novel means of inhibition of allergic or autoimmune responses was investigated. We showed that administration of protein or peptide antigens related to food allergens or self-antigens can efficiently inhibit antigen-specific immune responses in vivo. The use of anti-T-cell response was also shown to be effective in inhibiting autoimmune responses. We believe that the findings obtained in this study provide us with information useful not only for developing a novel way of treatment and prevention from allergies and autoimmune diseases but also for elucidating the mechanisms of oral tolerance, antigen recognition by immune system and onset of these diseases.

过敏或自身免疫性疾病的患者数量增加引起了人们对这些疾病的安全有效治疗方法的需求。我们旨在通过食物蛋白和肽及其氨基酸取代类似物来开发这种治疗。 1.在小鼠和对牛奶过敏的患者中分析了对食物过敏原的反应或自我抗原的同源物。 2.详细分析了β-乳球蛋白（一种主要的牛奶过敏原）的抗原结构。检查了β-乳球蛋白或其部分肽的单个氨基酸取代的类似物，检查其对过敏原特异性免疫反应的抑制作用，并被证明是有效的。此外，我们表明，另一种主要的牛奶过敏原的单一取代的肽的替代类似物可以调节对过敏原的CD8^+T细胞反应。 3.研究了口服耐受性所需的条件和机理。我们阐明了CD4^+T细胞，CD8^+T细胞和B细胞的作用，以及口服抗原的剂量与诱导口服耐受性之间的关系。此外，使用T细胞受体转基因小鼠分析了对口服抗原的免疫反应，包括肠道相关的淋巴组织的免疫反应。 4.研究了一种新型抑制过敏或自身免疫反应的方法。我们表明，与食物过敏原或自我抗原有关的蛋白质或肽抗原的给药可以有效抑制体内抗原特异性免疫反应。抗T细胞反应的使用也被证明可有效抑制自身免疫反应。我们认为，这项研究中获得的发现为我们提供了不仅有助于开发新型治疗和预防过敏和自身免疫性疾病的方法，还可以阐明口服耐受性的机制，免疫系统识别抗原和这些疾病的发作。

项目成果

K.Nishijima, M.Kohyama, T.Hisatsune, H.Kato, M.Kakehi and S.Kaminogawa: "Enhancing effect of interleukin-4 on the secretion of interferon-gamma by alpha_<s1>-casein-specific CD8^+ T cells." Biosci.Biotech.Biochem.61. 1156-1162 (1997)

K.Nishijima、M.Kohyama、T.Hisatsune、H.Kato、M.Kakehi 和 S.Kaminokawa：“通过 α_<s1>-酪蛋白特异性 CD8^ T 增强白细胞介素 4 对干扰素-γ 分泌的作用

H.Nakajima-Adachi, S.Hachimura, W.Ise, K.Honma, S.Nishiwaki, M.Hirota, N.Shimojo, T.Katsuki, A.Ametani, Y.Kohno, and S.Kaminogawa: "Determinant analysis of immunoglobulin E and immunoglobulin G4 antibodies and T cells specific for bovine d_<s1>-casein fro

H.Nakajima-Adachi、S.Hachimura、W.Ise、K.Honma、S.Nishiwaki、M.Hirota、N.Shimojo、T.Katsuki、A.Ametani、Y.Kohno 和 S.Kaminokawa：“行列式分析

Hirahara,K.et.al.: "Profound immunological tolerance in the antibody response against bovine α_<s1>-casein induced by intradermal administration of a dominant T cell determinant." Clin.Immunol.Immunopathol.76. 12-18 (1995)

Hirahara, K.et.al.：“皮内施用显性 T 细胞决定簇诱导的针对牛 α_<s1>-酪蛋白的抗体反应中具有深刻的免疫耐受性。”Clin.Immunol.Immunopathol.76（1995 年） ）

S.Kaminogawa.: "Food allergy, oral tolerance andimmunomodulation - their molecular and cellular mechanisms." Biosci.Biotech.Biochem.60. 1749-1756 (1996)

S.Kaminokawa.：“食物过敏、口服耐受和免疫调节——它们的分子和细胞机制。”

M.Totsuka, et al.: "Fine mapping of T-cell determinants of bovine β-lactoglobulin." Cytotechnology. 25. 101-110 (1997)

M. Totsuka 等人：“牛 β-乳球蛋白 T 细胞决定因素的精细定位。” 25. 101-110 (1997)