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患者数量的增加已经引起了对开发用于这些疾病的安全且有效的治疗手段的需求。我们的目标是通过食物蛋白质和肽以及它们的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或自身抗原的同源物的T细胞和B细胞应答。2.对牛乳中主要过敏原β-乳球蛋白的抗原结构进行了详细分析。β-乳球蛋白或其部分肽的单个氨基酸取代的类似物被检查其对变应原特异性免疫应答的抑制作用，并且显示出有效。此外，我们还发现α<s1>-酪蛋白（另一种主要的牛奶过敏原）的肽的单取代类似物可以调节CD 8 ^+ T细胞对过敏原的反应。3.探讨了口服耐受诱导的条件和机制。我们阐明了CD 4 ^+T细胞、CD 8 ^+T细胞和B细胞的作用，以及口服给药抗原剂量与口服耐受诱导之间的关系。此外，使用T细胞受体转基因小鼠分析了对口服给予的抗原的免疫应答，包括肠道相关淋巴组织的免疫应答。4.研究了一种新的抑制变态反应或自身免疫反应的方法。我们发现，给予与食物过敏原或自身抗原相关的蛋白质或肽抗原可以有效地抑制体内抗原特异性免疫应答。抗T细胞应答的使用也被证明在抑制自身免疫应答中是有效的。我们相信，本研究的结果不仅为开发治疗和预防过敏和自身免疫性疾病的新方法提供了有用的信息，而且还为阐明口服耐受、免疫系统识别抗原和这些疾病发病的机制提供了有用的信息。

项目成果

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)

T.Yoshida, S.Hachimura and S.Kaminogawa: "The oral administration of low-dose antigen induces activation followed by tolerization, while high-dose antigen induces tolerance without activation." Clin.Immunol.Immunopathol. 82. 207-215 (1997)

T.Yoshida、S.Hachimura 和 S.Kaminokawa：“口服低剂量抗原会诱导激活，然后产生耐受，而高剂量抗原会诱导耐受而不激活。”

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

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） ）