糸球体IgA沈着におけるTh2型粘膜免疫反応の役割 山中 貴博 玉内 秀一 鈴木 祐介 堀越 哲 寺島 正純 垣生 園子 富野 康日己 順天堂大学 順天堂医学 00226769 51 4 540 547 2005-12-30 目的:近年,Th1/Th2パラダイムに基づきIgA腎症の発症機序が検討されているが,いまだ明らかにされていない.今回われわれは,Th2型免疫誘導転写因子GATA-3遺伝子導入トランスジェニック(GATA-3 Tg)マウスを用いて糸球体へのIgA沈着における粘膜免疫の関わりについて検討した.対象:GATA-3 Tgと卵白アルブミン(OVA)認識T細胞レセプター遺伝子導入トランスジェニック(TCR-Tg)マウスとの交配によりGATA-3/TCR-Tgマウスを作製した.対照として,GATA-3遺伝子非導入WT/TCR-Tgマウスを用いた.方法:免疫方法は,経口免疫と腹腔免疫の2種類について検討した.経口免疫において,(I)OVA+コレラトキシン(CT)もしくは(II)CT単独,腹腔免疫では(III)OVA+アラム(Alum)を投与した.各々の群に対して最終感作から1週間後にOVAを追加経口投与し,4日後に各群の(1)血清OVA特異的IgA抗体価,(2)尿中アルブミン・クレアチニン量,(3)腎・腸管の病理組織学的検討を行った.結果:OVA+CTの経口免疫GATA-3/TCR-Tgマウスのみに,(1)IgA・C3の糸球体への沈着,(2)メサンギウム細胞増殖を伴う基質の拡大,(3)血清OVA特異的IgA抗体価の上昇,(4)IgAと同一部位にmannan-binding lectin (MBL)の沈着,(5)糸球体内にIgG2aの沈着などを認め,ヒトIgA腎症と極めて類似した所見を呈した.結論:IgAの腎糸球体への沈着は,Th2型免疫反応優位な環境下の粘膜免疫系を介して誘導されることが示唆された. 2005-12-30 110005858277 AN00113194 7796916 JPN CJP NDL NII-ELS 3 21 Glomerular IgA deposition through Th2-dominant mucosal immune responses YAMANAKA TAKAHIRO TAMAUCHI HIDEKAZU SUZUKI YUSUKE HORIKOSHI SATOSHI TERASHIMA MASAZUMI HABU SONOKO TOMINO YASUHIKO Juntendo University Juntendo medical journal Objective: The Th1/Th2 balance paradigm is considered related to the pathogenesis of IgA nephropathy. The present study investigated the mechanism of glomerular IgA deposition via mucosal immunity in several kinds of GATA-3 transgenic (GATA-3 Tg) mice, which have a Th2-dominant immunological background. Materials: The hemizygous GATA-3 Tg mice were crossed with the homozygous type of another transgenic (TCR-Tg) mouse for T cell receptor (TCR) recognizing OVA_<323-339> peptide in the context of I-A^d restriction. GATA-3/TCR-Tg and non-GATA-3 (WT) /TCR-Tg mice were generated by this method. Methods: Cholera enterotoxin (CT) was used as a mucosal adjuvant for Th2-dominant immune responses in oral immunization. Alum was used as an adjuvant for general immunopotentitation in intraperitoneal immunization. GATA-3/TCR-Tg mice and WT/TCR-Tg mice were orally preimmunized with OVA and CT or CT alone. The animals were orally immunized with OVA for 7 days after the final immunization. The levels of serum OVA-specific IgA antibody, urinary albumin and creatinine excretion and histopathological analysis of the kidney and intestine were examined. Measurement and Results: Only GATA-3/TCR-Tg mice that were orally immunized with OVA and CT showed mesangial proliferation with IgA/C3 depositions, the elevation of serum levels of OVA-specific IgA antibody, glomerular MBL deposition colocalized with IgA, and IgG2a deposition. These findings closely resemble clinical findings in human IgA nephropathy. Conclusions: The present data indicate that Th2-dependent mucosal immune responses may lead to glomerular IgA deposition, presumably through aberrant glycosylation of IgA. 山中 貴博 YAMANAKA TAKAHIRO 順天堂大学医学部内科学教室腎臓内科学講座 Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine 玉内 秀一 TAMAUCHI HIDEKAZU 北里大学医学部微生物学講座 Department of Microbiology, Kitasato University School of Medicine 鈴木 祐介 SUZUKI YUSUKE 順天堂大学医学部内科学教室腎臓内科学講座 Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine 堀越 哲 HORIKOSHI SATOSHI 順天堂大学医学部内科学教室腎臓内科学講座 Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine 寺島 正純 TERASHIMA MASAZUMI 住友製薬創薬第二研究所病態免疫 Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd 垣生 園子 HABU SONOKO 東海大学医学部防御機構系免疫学 Division of Host Defense Mechanism, Department of Immunology, Tokai University School of Medicine 富野 康日己 TOMINO YASUHIKO 順天堂大学医学部内科学教室腎臓内科学講座 Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine