Elucidation of properties and mechanism of development of autoimmune diseases in new congenic MRL/MpJ-lprcg/lprcg mice

阐明新同系 MRL/MpJ-lprcg/lprcg 小鼠自身免疫性疾病的特性和发生机制

• 批准号: 06454190
• 负责人: MATSUZAWA Akio
• 金额: $ 4.61万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454190/
• 关键词: mouse model; lpr^<cg> gene; MRL background; autoimmunity; congenic; gromeluronephritis; artiritis; lymphadenopathy; リンパ節腫脹; gld遺伝子; 相補作用

The novel lymphoproliferative and autoimmune lpr^<cg> gene, which we discovered in the CBA/KIJms (CBA) mice, was transferred onto the MRL/MpJ (MRL) background by 12 backcrosses. The resulting congenic MRL-lpr^<cg>/lpr^<cg> mice developed lymphoproliferative disease characterized by expansion of CD4-8-, Thy-1+, B220+ lymphoid cells (DN T cells). The histology of the kidney revealed that MRL-lpr^<cg>/lpr^<cg> mice developed glomerulonephritis indistinguishable from that in MRL-lpr/lpr although its frequency was slightly lower in the former. Glomerular immune complex deposition was almost the same in MRL-lpr^<cg>/lpr^<cg> and MRL-lpr/lpr mice. The levels of serum Ig, circulating immune complexes and autoantibodies in MRL-lpr^<cg>/lpr^<cg> were comparable to or even higher than those in MRL-lpr/lpr. Comparison between MRL-lpr^<cg>/lpr^<cg> with glomerulonephritis and CBA-lpr^<cg>/lpr^<cg> without it evidenced that the IgM-to-IgG class switch in class-specific autoantibody responses and serum Ig levels were enhanced in MRL-lpr^<cg>/lpr^<cg> as in MRL-lpr/lpr, Moreover, the function of the heterozygous lpr was investigated. MRL-lpr^<cg>/+ mice had significantly larger lymph nodes and spleens free from accumulation of anomalous DN T cells. Noticeably, the incidence and severity of gromeluronephritis were similar in MRL-lpr^<cg>/+ and -lpr^<cg>/lpr^<cg>, suggestive of no involvement of DN T cells in renal disease. These results taken together indicate that the lpr^<cg> functions through the same mehanism as lpr in induction of glomerulonephritis and serological abnormalities on the MRL background as expected from the allelism between both mutant genes and that the newly established conenic MRL-lpr^<cg>/lpr^<cg> mouse will provide a unique model for reserach into autoimmunity in mice.

我们<cg>在CBA/KIJms（CBA）小鼠中发现的新的淋巴增殖性和自身免疫性lpr^基因通过12次回交转移到MRL/MpJ（MRL）背景上。所得到的同源MRL-lpr^<cg>/lpr^<cg>小鼠发展出以CD 4 -8-、Thy-1+、B220+淋巴样细胞（DN T细胞）扩增为特征的淋巴组织增生性疾病。肾脏组织学显示，MRL-lpr^<cg>/lpr^<cg>小鼠发生的肾小球肾炎与MRL-lpr/lpr小鼠的肾小球肾炎难以区分，尽管前者的发生率略低。肾小球免疫复合物沉积在MRL-lpr^<cg>/lpr^<cg>和MRL-lpr/lpr小鼠中几乎相同。MRL-lpr ^ /lpr^的血清IG、循环免疫复合物和自身抗体水平<cg><cg>与MRL-lpr/lpr相当甚至更高。比较有肾小球肾炎的MRL-lpr^<cg>/lpr^<cg>与无肾小球肾炎的CBA-lpr^<cg>/lpr^<cg>，发现MRL-lpr^ /lpr^与MRL-lpr/lpr^一样，其类特异性自身抗体应答中IgM到IgG的类别转换和血清IG水平均增强<cg><cg>。MRL-lpr ^<cg>/+小鼠的淋巴结和脾脏明显较大，没有异常DN T细胞的聚集。值得注意的是，在MRL-lpr^ /+和-lpr^ /lpr^中肾小球肾炎的发生率和严重程度相似<cg><cg><cg>，提示DN T细胞在肾脏疾病中没有参与。这些结果共同表明，lpr^<cg>通过与lpr相同的机制诱导肾小球肾炎和MRL背景下的血清学异常，正如从两个突变基因之间的等位性所预期的，并且新建立的同源MRL-lpr^<cg>/lpr^<cg>小鼠将为研究小鼠自身免疫提供独特的模型。

项目成果

A. Suzuki: "Involvement of Fas in regression of vaginal epithelia after ovariectomy and during an estrous cycle" EMBO Journal. (In press). (1996)

A. Suzuki：“Fas 参与卵巢切除术后和动情周期内阴道上皮细胞退化”EMBO 杂志。

M.A.Mieza: "The selective reduction of Vα14+ NK T cells prededing disease development in autoimmune-prone mice" Journal of Experimental Medicine. (in press). (1996)

M.A.Mieza：“选择性减少 Vα14+ NK T 细胞预防自身免疫性小鼠疾病的发生”《实验医学杂志》（1996 年出版）。

M. A. Mieza: "The selective reduction of Vα14^+NK T cells preceding disease development in autoimmune-prone mice" Journal Experimental Medicine. (In press). (1996)

M. A. Mieza：“自身免疫性小鼠疾病发生前选择性减少 Vα14^+NK T 细胞”实验医学杂志（1996 年）。

Miez, M.A., Itoh, T., Cui, J.Q., Makino, Y., Tsuchida, K., Koike, T., Shiral, H., Yagita, H., Mtsuzawa A., Koyasu, S., Koseki, H.and Taniguchi, T.: "The selective reduction of V 14+ NK T cells preceding disease development in autoimmuneprone mice." J.Ex.M

Miez, M.A.、Itoh, T.、Cui, J.Q.、Makino, Y.、Tsuchida, K.、Koike, T.、Shiral, H.、Yagita, H.、Mtsuzawa A.、Koyasu, S.、Koseki, H

J.L.Chu: "Massive upregulation of the Fas ligand in lpr and gld mice: Implications for Fas regulation and the graft-v-disease like ws" Journal of Experimental Medicene. 181. 393-398 (1995)

J.L.Chu：“lpr 和 gld 小鼠中 Fas 配体的大量上调：对 Fas 调节和 ws 等移植物 V 病的影响”《实验医学杂志》。