Role of T Cells (Thymus) in H-2-Linked Control of Autoimmune Disease

T 细胞（胸腺）在 H-2 连锁控制自身免疫性疾病中的作用

• 批准号: 01570269
• 负责人: ONO Shiro
• 金额: $ 1.34万
• 依托单位: Osaka University Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570269/
• 关键词: Autoimmune disease; H-2-linked control; (NZBxNZW)F1 mice; Thymus graft; Radiation-induced bone marrow chimera; T-cell repertoire; 自己免疾疾患; Hー2遺伝子; (NZB×NZW)F1ヌ-ドマウス; H-2遺伝子

The development of human systemic lupus erythematosus (SLE) -like disease in (NZB x NZW) F1 (BWF1, H-2^<d/z>) mice was thought to be resulted primarily from their hyper-reactivity of B cell-function. However, We have demonstrated recently that congenitally athymic BWF1 nude mice fail to develop the disease, and that the engrafting thymus from BWF1 mice into BWF1 nude mice manifest the SLE-like disease. These results indicate the obligatory requirement fot thymus (T cells) in the development of autoimmune disease in BWF1 mice. Although it has been shown that H-2 gene products NZW mice play a crucial role in the onset of autoimmune disease in BWF1 mice, the mechanisms underlying the H-2-linked control are not clear at present.This study was undertaken to investigate the possible association of thymic genotype with autoimmune manifestations in BWF1 mice by utilizing BWF1 nude mice engrafted with NZB (H-2^d), NZW (H-2^z), or BWF1 thymus. The development of SLE-like disease characterized by spontaneous production of anti-ssDNA IgG antibodies and appearance of proteinuria was retarded in BWF1 nude mice engrafted with NZB thymus as compared to those engrafted with NZW or BWF1 mice, suggesting a crucial role of thymic H-2 genotype the disease. Moreover, T cells derived from lethally irradiated NZW or BWF1 mice reconstituted with BWF1 bone marrow cells ( BWF1->NZW or BWF1->BWF1 chimeras ) exhibited high helper activities capable of inducing in vitro anti-ssDNA IgG antibodies, while such a helper activity was not detected in T cells from BWF1->NZB chimeras.The present results support the notion that the H-2-linked control of autoimmune disease in BWF1 mice is attributable to the influence of H-2 genotype of thymus on the generation of helper T cells responsible for auto-antibody production of IgG class.

在（NZB x NZW） F1 （BWF1, H-2^<d/z>）小鼠中，人系统性红斑狼疮（SLE）样疾病的发展被认为主要是由B细胞功能的高反应性引起的。然而，我们最近证明先天性胸腺缺陷的BWF1裸鼠不会发生这种疾病，并且从BWF1小鼠移植胸腺到BWF1裸鼠中表现出sle样疾病。这些结果表明胸腺（T细胞）在BWF1小鼠自身免疫性疾病的发展中具有强制性需求。虽然已有研究表明H-2基因产物NZW小鼠在BWF1小鼠自身免疫性疾病的发病中起着至关重要的作用，但目前H-2连锁控制的机制尚不清楚。本研究通过植入NZB （H-2^d）、NZW （H-2^z）或BWF1胸腺的BWF1裸鼠，探讨胸腺基因型与BWF1小鼠自身免疫表现的可能关联。与植入NZW或BWF1小鼠相比，植入NZB胸腺的BWF1裸鼠以自发产生抗ssdna IgG抗体和出现蛋白尿为特征的slea样疾病的发展被延缓，这表明胸腺H-2基因型在该疾病中起关键作用。此外，用BWF1骨髓细胞（BWF1->NZW或BWF1->BWF1嵌合体）重组的致死辐照的NZW或BWF1小鼠的T细胞显示出高的辅助活性，能够诱导体外抗ssdna IgG抗体，而在BWF1->NZB嵌合体的T细胞中没有检测到这种辅助活性。目前的结果支持这样一种观点，即BWF1小鼠自身免疫性疾病的H-2连锁控制可归因于胸腺H-2基因型对负责产生IgG类自身抗体的辅助性T细胞产生的影响。

项目成果

K.Miyake et al.: "Monoclonal antibodies to Pgp-1/CD44 block lymphohemopoiesis in long-term bone marrow cultures" J.Exp.Med.171. 477-488 (1990)

K.Miyake 等人：“Pgp-1/CD44 的单克隆抗体可阻断长期骨髓培养物中的淋巴造血作用”J.Exp.Med.171。

K.Ishihara et sl.: "Different effect of prostaglandin E2 on Bーcell activation by two distinct Bーcell differentiation factors, B151ーTRF1/ILー5 and B151ーTRF2:Selective inhibition of B151ーTRF2ーinducued antiboay response through increases in intracellular cycl

K.Ishihara 等人：“前列腺素 E2 对两种不同 B 细胞分化因子 B151-TRF1/IL-5 和 B151-TRF2 对 B 细胞激活的不同影响：通过选择性抑制 B151-TRF2 诱导的抗体反应细胞内周期增加

Y.Takahama et al.: "Disparate functions of IーA and IーE molecules on B cells as evidenced by the inhibition with antiーIーA and antiーIーE antibodies of polyclonal B cell activation" Eur.J.Immunol.19. 2227-2235 (1989)

Y.Takahama 等人：“通过抗 I-A 和抗 I-E 抗体对多克隆 B 细胞活化的抑制证明了 I-A 和 I-E 分子在 B 细胞上的不同功能”Eur.J.19。 1989）

K.Miyake,et al.: "Monoclonal antibodies to Pgpー1/CD44 block lymphoーhemopoiesis in long term bone marrow cultures" J.Exp.Med.171. 477-488 (1990)

K. Miyake 等人：“Pgp-1/CD44 的单克隆抗体可阻断长期骨髓培养物中的淋巴造血”J.Exp.Med.171（1990）。

K.Ishihara: "Different effect of prostaglandin E2 on Bーcell activation by two distinct B cell differentiation factors,B151ーTRF1/ILー5 and B151ーTRF2:selective inhibition of B151ーTRF2ーinduced antibody response through increasesin intracellular cAMP lerels."

K.Ishihara：“前列腺素 E2 对两种不同 B 细胞分化因子 B151-TRF1/IL-5 和 B151-TRF2 激活 B 细胞的不同作用：通过增加细胞内 cAMP 值选择性抑制 B151-TRF2 诱导的抗体反应”。