1995 Fiscal Year Annual Research Report

IL-2受容体γ鎖変異による伴性重症複合免疫不全症の発症機構に関する研究

Research Project

Project/Area Number	06404025
Research Institution	Tohoku University
Principal Investigator	菅村和夫東北大学, 医学部, 教授 (20117360)
Co-Investigator(Kenkyū-buntansha)	笠井憲雪東北大学, 医学部, 教授 (60001947) 今野多助東北大学, 加齢医学研究所, 教授 (00004846) 浅尾裕信東北大学, 医学部, 助手 (80250744)
Keywords	インターロイキン2(IL-2) / IL-2受容体 / サイトカイン / XSCID / T細胞分化増殖 / γ鎖ノックアウトマウス
Research Abstract	ヒト伴性重症複合免疫不全症(XSCID)はインターロイキン2(IL-2)受容体γ鎖遺伝子の変異に伴うT細胞初期分化過程の障害が原因である。このXSCID発症機構を詳細に解析するために、γ鎖を共通受容体とするサイトカイン受容体からの細胞内シグナル伝達機構について解析した。その結果、γ鎖を共有するIL-2、IL-4、IL-7、IL-9の各サイトカインの刺激によって、Jak1ならびにJak3チロシンキナーゼの活性化がみられた。さらに、IL-2受容体β鎖に会合するLAK1チロシンキナーゼがIL-4、IL-7、IL-9の各受容体のα鎖にも会合していることを明らかにした。このJAK1の会合はIL-2受容体β鎖および上記各サイトカイン受容体のα鎖の細胞内領域に共通に存在するbox1領域を介していることが分かった。MOLT4細胞にbox1変異IL-2受容体β鎖を遺伝子導入し、細胞増殖シグナルとJak1およびJak3との関連性を調べたところ、Jak1の会合ならびに活性化はIL-2による細胞増殖シグナル伝達には必須ではないことが明らかになった。さらに、Jak3の活性化にもJak1は必須では内ことが分かった。他方、γ鎖変異マウスを作出し、これらマウスでの血液病理組織学的、免疫学的検索を行った。その結果、同マウスはT,B細胞の著減とNK細胞の消失を伴い、免疫不全状態にあることが分かった。さらに、髄外造血の亢進がみられ、生体内におけるγ鎖の機能の多様性が示唆された。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Ishii,N.: "mAb specific for the γ chain of the IL-2 receptor." Leucocyte Typing V. 2. 1867-1868 (1995)
[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex." Inter.Immunol.7. 115-120 (1995)
[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ subunit in IL-4-dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.25. 126-131 (1995)
[Publications] Oubo,K.: "Functional analysis of the human interleukin 2 receptor γ chain gene promoter." J.Biol.Chem.270. 7479-7486 (1995)
[Publications] Sugamura,K.,: "The common γ chain for multiple cytokine receptors." Adv.Immunol.59. 225-277 (1995)
[Publications] Moreau,J.L.: "Control by interleukin-2 and interleukin-4 of the IL-2 responsiveness of murine B cells." J.Immunol.155. 3401-3408 (1995)
[Publications] Kumaki,S.: "Characterization of B cell lines established from two X-linked severe combined immunodificiency patients:interleukin-15 binds to the B cells but not internalized efficiently." Blood. 86. 1428-1436 (1995)
[Publications] Nemoto,T.: "Difference in interleukin 2(IL-2) receptor system between human and mouse:essential requirement of the α chain for formation of the functional mouse IL-2 receptor." Eur.J.Immunol.25. 3001-3005 (1995)
[Publications] Clark,C.J.P.: "Interleukin 4 inhibits κ light chain expression and NFκB activation but not IkBa degradation in 70Z/3 murine pre-B cells." Eur.J.Immunol.25. 2961-2966 (1995)
[Publications] Edelbaum,D.: "Interleukin(IL)-15 promotes the growth of murine epidermal γδ T cells by a mechanism involving the β-and γc-chains of the IL-2 receptor." J.Invest.Dermatol.-105. 837-843 (1995)
[Publications] Ohbo,K.: "Modulation of hematopoiesis in mouse with a truncated mutant of the interleukin-2 receptor γ chain." Blood. 87. 956-967 (1995)
[Publications] Sugamura,K.: "The interleukin 2 receptor γ chain:its role in the multiple cytokine receptor complexes and T cell development in XSCID." Annu.Rev.Immunol.14. 179-205 (1996)
[Publications] Saito,S.: "Expression of the interleukin-2 receptor(IL-2R)γ chain on cord blood mononuclear cells." Blood. (in press.).
[Publications] Schnyder,B.: "IL-4 and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common γ chain(γc)." Blood. (in press).
[Publications] Ohbo,K.: "Demonstration of a crosstalk between IL-2 and IL-5 in phosphorylation of IL-2 and IL-5 receptor β chains." Inter.Immunol.(in press.).

1995 Fiscal Year Annual Research Report

IL-2受容体γ鎖変異による伴性重症複合免疫不全症の発症機構に関する研究

Principal Investigator

菅村 和夫 東北大学, 医学部, 教授 (20117360)

Research Products

[Publications] Ishii,N.: "mAb specific for the γ chain of the IL-2 receptor." Leucocyte Typing V. 2. 1867-1868 (1995)

[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex." Inter.Immunol.7. 115-120 (1995)

[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ subunit in IL-4-dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.25. 126-131 (1995)

[Publications] Oubo,K.: "Functional analysis of the human interleukin 2 receptor γ chain gene promoter." J.Biol.Chem.270. 7479-7486 (1995)

[Publications] Sugamura,K.,: "The common γ chain for multiple cytokine receptors." Adv.Immunol.59. 225-277 (1995)

[Publications] Moreau,J.L.: "Control by interleukin-2 and interleukin-4 of the IL-2 responsiveness of murine B cells." J.Immunol.155. 3401-3408 (1995)

[Publications] Kumaki,S.: "Characterization of B cell lines established from two X-linked severe combined immunodificiency patients:interleukin-15 binds to the B cells but not internalized efficiently." Blood. 86. 1428-1436 (1995)

[Publications] Nemoto,T.: "Difference in interleukin 2(IL-2) receptor system between human and mouse:essential requirement of the α chain for formation of the functional mouse IL-2 receptor." Eur.J.Immunol.25. 3001-3005 (1995)

[Publications] Clark,C.J.P.: "Interleukin 4 inhibits κ light chain expression and NFκB activation but not IkBa degradation in 70Z/3 murine pre-B cells." Eur.J.Immunol.25. 2961-2966 (1995)

[Publications] Edelbaum,D.: "Interleukin(IL)-15 promotes the growth of murine epidermal γδ T cells by a mechanism involving the β-and γc-chains of the IL-2 receptor." J.Invest.Dermatol.-105. 837-843 (1995)

[Publications] Ohbo,K.: "Modulation of hematopoiesis in mouse with a truncated mutant of the interleukin-2 receptor γ chain." Blood. 87. 956-967 (1995)

[Publications] Sugamura,K.: "The interleukin 2 receptor γ chain:its role in the multiple cytokine receptor complexes and T cell development in XSCID." Annu.Rev.Immunol.14. 179-205 (1996)

[Publications] Saito,S.: "Expression of the interleukin-2 receptor(IL-2R)γ chain on cord blood mononuclear cells." Blood. (in press.).

[Publications] Schnyder,B.: "IL-4 and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common γ chain(γc)." Blood. (in press).

[Publications] Ohbo,K.: "Demonstration of a crosstalk between IL-2 and IL-5 in phosphorylation of IL-2 and IL-5 receptor β chains." Inter.Immunol.(in press.).

菅村和夫東北大学, 医学部, 教授 (20117360)