TACI-Ig对ConA活化淋巴细胞的染色质诱导SLE样小鼠模型的治疗作用
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摘要
目的:
建立刀豆蛋白A(concanavalin A, ConA)活化淋巴细胞的染色质诱导的系统性红斑狼疮(systemic lupus erythematosus, SLE)样小鼠模型,观察B淋巴细胞刺激因子受体TACI融合蛋白(TACI-immunoglobulin, TACI-Ig)隔日一次皮下注射给药8周对模型小鼠的治疗作用,并探讨其部分作用机制。
方法:
用ConA活化淋巴细胞的染色质诱导SLE样小鼠模型,d28起以TACI-Ig(3.75,7.5,15mg·kg~(-1))隔日一次皮下注射给药8周,观察小鼠一般体征变化,目测半定量尿蛋白试纸法检测动物的尿蛋白变化,HE染色法检查动物肾脏、脾脏病理改变,计算动物的脾脏和胸腺指数,3~H-TdR掺入法检测脂多糖(lipopolysaccharide, LPS)和ConA诱导的B和T淋巴细胞增殖反应,全自动生化分析仪检测血清中Crea和BUN水平,酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测小鼠血清中ANA、anti-dsDNA、IgG1、IgG2a、BLyS、IL-10和IFN-γ水平,流式细胞术检测脾脏T、B淋巴细胞亚群变化。
结果:
1. TACI-Ig皮下注射给药对SLE样模型小鼠一般体征及尿蛋白的影响模型小鼠在给药开始后5~8周时被毛疏松,光泽度下降。TACI-Ig皮下注射给药各组动物在给药期间行为活泼,毛发较模型组动物有光泽。模型小鼠尿蛋白水平随着造模后时间的延长而逐渐升高,TACI-Ig(15mg·kg~(-1))隔日一次皮下注射给药第4~8周、TACI-Ig(7.5mg·kg~(-1))隔日一次皮下注射给药第6~8周均可显著降低模型动物的尿蛋白水平。
2. TACI-Ig皮下注射给药对SLE样模型小鼠的肾脏、脾脏组织病理学的影响模型小鼠具有明显的间质性肾炎特征,肾小球体积增大,系膜细胞增生,系膜基质增多,肾小球玻璃样变性,局部中性粒细胞浸润,毛细血管基底膜略增厚;脾脏白髓弥漫性增生,中央动脉管壁纤维性增厚,生发中心形成。TACI-Ig皮下注射给药后模型小鼠的肾小球体积减小,肾小球系膜细胞增生减少,肾间质出血、中性粒细胞浸润等炎症状态有明显改善。TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药能明显减少脾脏生发中心的形成,有效改善白髓增生。
3. TACI-Ig皮下注射给药对SLE样模型小鼠胸腺指数和脾脏指数的影响模型小鼠的脾脏指数较正常小鼠显著升高,胸腺指数无明显改变,TACI-Ig(15mg·kg~(-1))皮下注射给药可显著降低SLE样模型小鼠异常升高的脾脏指数。
4. TACI-Ig皮下注射给药对SLE样模型小鼠胸腺淋巴细胞和脾淋巴细胞增殖的影响模型小鼠的脾淋巴细胞增殖反应较对照组显著增强,TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药可显著降低模型小鼠LPS诱导的脾脏B淋巴细胞增殖反应,而对ConA诱导的胸腺T淋巴细胞增殖则无明显影响。
5. TACI-Ig皮下注射给药对SLE样模型小鼠肾功能的影响模型小鼠血清Crea和BUN水平比对照组BALB/c小鼠显著升高,TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药能显著降低模型小鼠的Crea和BUN水平。
6. TACI-Ig皮下注射给药对SLE样模型小鼠血清ANA、anti-dsDNA、IgG1和IgG2a的影响
模型小鼠的血清ANA、anti-dsDNA、IgG1和IgG2a水平显著升高,TACI-Ig皮下注射给药对模型小鼠升高的ANA、anti-dsDNA、IgG1和IgG2a水平均有显著降低作用。
7. TACI-Ig皮下注射给药对SLE样模型小鼠血清BLyS、IL-10、IFN-γ的影响模型小鼠血清的BLyS、IL-10、IFN-γ水平显著升高,TACI-Ig(3.75,7.5,15mg·kg~(-1))皮下注射给药均可显著下调BLyS水平,TACI-Ig(15mg·kg~(-1))皮下注射给药可显著降低IL-10水平,TACI-Ig给药对模型小鼠的IFN-γ水平无明显影响。
8. TACI-Ig皮下注射给药对SLE样模型小鼠脾脏T、B淋巴细胞亚群的影响模型小鼠的脾脏总B淋巴细胞(CD19~+),活化B淋巴细胞(CD19~+CD21~+,CD19~+CD23~+),成熟B淋巴细胞(CD19~+IgD~+)的百分比显著升高,而记忆B淋巴细胞(CD19~+CD27~+)和早期B淋巴细胞(CD19~+IgM~+)的表达与对照组比较差异无显著性。TACI-Ig(3.75,7.5,15mg·kg~(-1))皮下注射给药能显著降低模型小鼠总B淋巴细胞,活化B淋巴细胞,成熟B淋巴细胞和早期B淋巴细胞的百分比,而对记忆B淋巴细胞表达无明显影响。模型组小鼠T淋巴细胞各亚群的百分比与对照组无明显差异。TACI-Ig(15mg·kg~(-1))皮下注射给药可以显著升高活化Th淋巴细胞(CD4~+CD25~+)百分比,而对Th淋巴细胞其它亚群的表达无明显影响。
结论:
1. TACI-Ig皮下注射给药对活性染色质诱导的SLE样模型小鼠具有治疗作用,可有效改善小鼠的肾功能,降低小鼠的蛋白尿水平,明显改善模型小鼠肾小球肾炎和脾脏增生等病理变化。
2. TACI-Ig皮下注射给药可有效减少脾脏总B淋巴细胞、活化B淋巴细胞和成熟B淋巴细胞数量,显著降低升高的自身抗体和炎性细胞因子水平,提示其作用机制与调节免疫功能有关。
OBJECTIVE
Systemic lupus erythematosus (SLE)-like mouse model was successfully established by immunizing with active chromatin isolated from concanavalin A (ConA)- activated lymphocytes. We observed the therapeutic effects of B lymphocyte stimulator receptor TACI fusion protein (TACI-Ig) subcutaneously once every other day for 8 weeks on model mice and investigated its partly mechanism.
METHODS
SLE-like mouse model was successfully established by immunized with active chromatin isolated from ConA-actived lymphocytes. Mice were treated with TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously once every other day from d28 for 8 weeks. General signs were observed. Proteinuria was measured by Semi-quantitative Albustix paper. Histopathological changes of kidney and spleen were observed by haematoxylin and eosine (HE) staining. Thymus index and spleen index were calculated. Thymo-lymphocyte and spleno-lymphocyte proliferation stimulated by ConA and lipopolysaccharide (LPS) were tested by 3H-TdR incorporation method. Levels of Crea and BUN were detected by automatic biochemical analyzer. Levels of ANA, anti-dsDNA, IgG1, IgG2a, BLyS, IL-10 and IFN-γin serum were tested by enzyme-linked immunosorbent assay (ELISA). Splenic T, B lymphocyte subsets were analysed by flow cytometry.
RESULTS
1. Effect of TACI-Ig on general signs and urine protein
Model mice showed hair loose and glossiness decline from 5-8 weeks, while mice treated with TACI-Ig subcutaneously bahaved actively and had more glossy hair than model group.
The level of urine protein of model group gradually improved over time. TACI-Ig (15mg·kg~(-1)) subcutaneously once every other day from 4-8 week and TACI-Ig (7.5mg·kg~(-1)) subcutaneously once every other day from 6-8 week could reduce the level of urine protein of the SLE-like model mice significantly.
2. Effect of TACI-Ig on kidney and spleen histopathology
Kidney sections from model group showed obvious features of interstitial nephritis, glomerular volume and mesangial matrix increasing, mesangial cell hyperplasia, glomerular hyaline degeneration, local neutrophil infiltration, capillary basement membrane thickening slightly. Spleen sections from model group showed diffuse hyperplasia of the spleen white pulp, central arterial wall fibrous thickening and germinal centers formation. TACI-Ig subcutaneously markedly reduced glomerular volume, decreased mesangial cell hyperplasia, effectively improved renal interstitial hemorrhage, neutrophil infiltration and other inflammatory state. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously evidently reduced the formation of splenic germinal centers and improved the hyperplasia of white pulp.
3. Effect of TACI-Ig on thymus index and spleen index
Spleen index of model group rose strikingly compared with normal group, but no obvious changes on thymus index were observed. TACI-Ig (15mg·kg~(-1)) subcutaneously could decrease the elevated spleen index of model group significantly.
4. Effect of TACI-Ig on thymo-lymphocyte and spleno-lymphocyte proliferation
Spleno-lymphocyte proliferation was higher in model group compared with that in control group. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously could decrease spleno-lymphocyte proliferation of the model mice stimulated by LPS obviously, but had no significant effect on thymo-lymphocyte proliferation stimulated by ConA.
5. Effect of TACI-Ig on renal function
The levels of Crea and BUN increased significantly in serum of model group compared with control group. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously could decrease the elevated levels of Crea and BUN.
6. Effect of TACI-Ig on levels of ANA, anti-dsDNA, IgG1 and IgG2a in serum
The levels of ANA, anti-dsDNA, IgG1 and IgG2a increased significantly in serum of model group compared with control group. TACI-Ig subcutaneously could decrease the elevated levels of ANA, anti-dsDNA, IgG1 and IgG2a.
7. Effect of TACI-Ig on levels of BLyS, IL-10, IFN-γin serum
The levels of BLyS, IL-10, IFN-γin serum of model group increased obviously. TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously could reduce the level of BLyS evidently. TACI-Ig (15mg·kg~(-1)) subcutaneously could reduce the level of IL-10 markedly. TACI-Ig administration had no significant effect on the level of IFN-γin model mice.
8. Effect of TACI-Ig on splenic T, B lymphocyte subsets
The percentage of total B cells (CD19~+), activated B cells (CD19~+CD21~+, CD19~+CD23~+) and mature B cells (CD19~+IgD~+) in spleen elevated significantly in model group compared with control group except immature B cells (CD19~+IgM~+) and memory B cells (CD19~+CD27~+). Mice treated with TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously could decrease the percentage of total B cells, activated B cells, mature B cells and immature B cells, but with no significant effect on memory B cells.
The percentage of T cell subsets in model group had no significant differences compared with control group. TACI-Ig (15mg·kg~(-1)) subcutaneously could elevate the percentage of activated Th cells (CD4~+CD25~+), but had no significant effect on other subsets of Th cells.
CONCLUSIONS
1. TACI-Ig subcutaneously had a therapeutic effect on SLE-like mouse model induced by active chromatin. It could improve renal function effectively, reduce the level of urine protein, ameliorate the pathological changes such as interstitial nephritis and spleen hyperplasia of model mice obviously.
2. TACI-Ig subcutaneously could decrease the percentage of total B cells, activated B cells and mature B cells effectively and reduce the elevated levels of autoantibodies and inflammatory cytokines evidently, which prompt that its mechanism may be related with the regulation of immune function.
建立刀豆蛋白A(concanavalin A, ConA)活化淋巴细胞的染色质诱导的系统性红斑狼疮(systemic lupus erythematosus, SLE)样小鼠模型,观察B淋巴细胞刺激因子受体TACI融合蛋白(TACI-immunoglobulin, TACI-Ig)隔日一次皮下注射给药8周对模型小鼠的治疗作用,并探讨其部分作用机制。
方法:
用ConA活化淋巴细胞的染色质诱导SLE样小鼠模型,d28起以TACI-Ig(3.75,7.5,15mg·kg~(-1))隔日一次皮下注射给药8周,观察小鼠一般体征变化,目测半定量尿蛋白试纸法检测动物的尿蛋白变化,HE染色法检查动物肾脏、脾脏病理改变,计算动物的脾脏和胸腺指数,3~H-TdR掺入法检测脂多糖(lipopolysaccharide, LPS)和ConA诱导的B和T淋巴细胞增殖反应,全自动生化分析仪检测血清中Crea和BUN水平,酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测小鼠血清中ANA、anti-dsDNA、IgG1、IgG2a、BLyS、IL-10和IFN-γ水平,流式细胞术检测脾脏T、B淋巴细胞亚群变化。
结果:
1. TACI-Ig皮下注射给药对SLE样模型小鼠一般体征及尿蛋白的影响模型小鼠在给药开始后5~8周时被毛疏松,光泽度下降。TACI-Ig皮下注射给药各组动物在给药期间行为活泼,毛发较模型组动物有光泽。模型小鼠尿蛋白水平随着造模后时间的延长而逐渐升高,TACI-Ig(15mg·kg~(-1))隔日一次皮下注射给药第4~8周、TACI-Ig(7.5mg·kg~(-1))隔日一次皮下注射给药第6~8周均可显著降低模型动物的尿蛋白水平。
2. TACI-Ig皮下注射给药对SLE样模型小鼠的肾脏、脾脏组织病理学的影响模型小鼠具有明显的间质性肾炎特征,肾小球体积增大,系膜细胞增生,系膜基质增多,肾小球玻璃样变性,局部中性粒细胞浸润,毛细血管基底膜略增厚;脾脏白髓弥漫性增生,中央动脉管壁纤维性增厚,生发中心形成。TACI-Ig皮下注射给药后模型小鼠的肾小球体积减小,肾小球系膜细胞增生减少,肾间质出血、中性粒细胞浸润等炎症状态有明显改善。TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药能明显减少脾脏生发中心的形成,有效改善白髓增生。
3. TACI-Ig皮下注射给药对SLE样模型小鼠胸腺指数和脾脏指数的影响模型小鼠的脾脏指数较正常小鼠显著升高,胸腺指数无明显改变,TACI-Ig(15mg·kg~(-1))皮下注射给药可显著降低SLE样模型小鼠异常升高的脾脏指数。
4. TACI-Ig皮下注射给药对SLE样模型小鼠胸腺淋巴细胞和脾淋巴细胞增殖的影响模型小鼠的脾淋巴细胞增殖反应较对照组显著增强,TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药可显著降低模型小鼠LPS诱导的脾脏B淋巴细胞增殖反应,而对ConA诱导的胸腺T淋巴细胞增殖则无明显影响。
5. TACI-Ig皮下注射给药对SLE样模型小鼠肾功能的影响模型小鼠血清Crea和BUN水平比对照组BALB/c小鼠显著升高,TACI-Ig(7.5,15mg·kg~(-1))皮下注射给药能显著降低模型小鼠的Crea和BUN水平。
6. TACI-Ig皮下注射给药对SLE样模型小鼠血清ANA、anti-dsDNA、IgG1和IgG2a的影响
模型小鼠的血清ANA、anti-dsDNA、IgG1和IgG2a水平显著升高,TACI-Ig皮下注射给药对模型小鼠升高的ANA、anti-dsDNA、IgG1和IgG2a水平均有显著降低作用。
7. TACI-Ig皮下注射给药对SLE样模型小鼠血清BLyS、IL-10、IFN-γ的影响模型小鼠血清的BLyS、IL-10、IFN-γ水平显著升高,TACI-Ig(3.75,7.5,15mg·kg~(-1))皮下注射给药均可显著下调BLyS水平,TACI-Ig(15mg·kg~(-1))皮下注射给药可显著降低IL-10水平,TACI-Ig给药对模型小鼠的IFN-γ水平无明显影响。
8. TACI-Ig皮下注射给药对SLE样模型小鼠脾脏T、B淋巴细胞亚群的影响模型小鼠的脾脏总B淋巴细胞(CD19~+),活化B淋巴细胞(CD19~+CD21~+,CD19~+CD23~+),成熟B淋巴细胞(CD19~+IgD~+)的百分比显著升高,而记忆B淋巴细胞(CD19~+CD27~+)和早期B淋巴细胞(CD19~+IgM~+)的表达与对照组比较差异无显著性。TACI-Ig(3.75,7.5,15mg·kg~(-1))皮下注射给药能显著降低模型小鼠总B淋巴细胞,活化B淋巴细胞,成熟B淋巴细胞和早期B淋巴细胞的百分比,而对记忆B淋巴细胞表达无明显影响。模型组小鼠T淋巴细胞各亚群的百分比与对照组无明显差异。TACI-Ig(15mg·kg~(-1))皮下注射给药可以显著升高活化Th淋巴细胞(CD4~+CD25~+)百分比,而对Th淋巴细胞其它亚群的表达无明显影响。
结论:
1. TACI-Ig皮下注射给药对活性染色质诱导的SLE样模型小鼠具有治疗作用,可有效改善小鼠的肾功能,降低小鼠的蛋白尿水平,明显改善模型小鼠肾小球肾炎和脾脏增生等病理变化。
2. TACI-Ig皮下注射给药可有效减少脾脏总B淋巴细胞、活化B淋巴细胞和成熟B淋巴细胞数量,显著降低升高的自身抗体和炎性细胞因子水平,提示其作用机制与调节免疫功能有关。
OBJECTIVE
Systemic lupus erythematosus (SLE)-like mouse model was successfully established by immunizing with active chromatin isolated from concanavalin A (ConA)- activated lymphocytes. We observed the therapeutic effects of B lymphocyte stimulator receptor TACI fusion protein (TACI-Ig) subcutaneously once every other day for 8 weeks on model mice and investigated its partly mechanism.
METHODS
SLE-like mouse model was successfully established by immunized with active chromatin isolated from ConA-actived lymphocytes. Mice were treated with TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously once every other day from d28 for 8 weeks. General signs were observed. Proteinuria was measured by Semi-quantitative Albustix paper. Histopathological changes of kidney and spleen were observed by haematoxylin and eosine (HE) staining. Thymus index and spleen index were calculated. Thymo-lymphocyte and spleno-lymphocyte proliferation stimulated by ConA and lipopolysaccharide (LPS) were tested by 3H-TdR incorporation method. Levels of Crea and BUN were detected by automatic biochemical analyzer. Levels of ANA, anti-dsDNA, IgG1, IgG2a, BLyS, IL-10 and IFN-γin serum were tested by enzyme-linked immunosorbent assay (ELISA). Splenic T, B lymphocyte subsets were analysed by flow cytometry.
RESULTS
1. Effect of TACI-Ig on general signs and urine protein
Model mice showed hair loose and glossiness decline from 5-8 weeks, while mice treated with TACI-Ig subcutaneously bahaved actively and had more glossy hair than model group.
The level of urine protein of model group gradually improved over time. TACI-Ig (15mg·kg~(-1)) subcutaneously once every other day from 4-8 week and TACI-Ig (7.5mg·kg~(-1)) subcutaneously once every other day from 6-8 week could reduce the level of urine protein of the SLE-like model mice significantly.
2. Effect of TACI-Ig on kidney and spleen histopathology
Kidney sections from model group showed obvious features of interstitial nephritis, glomerular volume and mesangial matrix increasing, mesangial cell hyperplasia, glomerular hyaline degeneration, local neutrophil infiltration, capillary basement membrane thickening slightly. Spleen sections from model group showed diffuse hyperplasia of the spleen white pulp, central arterial wall fibrous thickening and germinal centers formation. TACI-Ig subcutaneously markedly reduced glomerular volume, decreased mesangial cell hyperplasia, effectively improved renal interstitial hemorrhage, neutrophil infiltration and other inflammatory state. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously evidently reduced the formation of splenic germinal centers and improved the hyperplasia of white pulp.
3. Effect of TACI-Ig on thymus index and spleen index
Spleen index of model group rose strikingly compared with normal group, but no obvious changes on thymus index were observed. TACI-Ig (15mg·kg~(-1)) subcutaneously could decrease the elevated spleen index of model group significantly.
4. Effect of TACI-Ig on thymo-lymphocyte and spleno-lymphocyte proliferation
Spleno-lymphocyte proliferation was higher in model group compared with that in control group. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously could decrease spleno-lymphocyte proliferation of the model mice stimulated by LPS obviously, but had no significant effect on thymo-lymphocyte proliferation stimulated by ConA.
5. Effect of TACI-Ig on renal function
The levels of Crea and BUN increased significantly in serum of model group compared with control group. TACI-Ig (7.5, 15mg·kg~(-1)) subcutaneously could decrease the elevated levels of Crea and BUN.
6. Effect of TACI-Ig on levels of ANA, anti-dsDNA, IgG1 and IgG2a in serum
The levels of ANA, anti-dsDNA, IgG1 and IgG2a increased significantly in serum of model group compared with control group. TACI-Ig subcutaneously could decrease the elevated levels of ANA, anti-dsDNA, IgG1 and IgG2a.
7. Effect of TACI-Ig on levels of BLyS, IL-10, IFN-γin serum
The levels of BLyS, IL-10, IFN-γin serum of model group increased obviously. TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously could reduce the level of BLyS evidently. TACI-Ig (15mg·kg~(-1)) subcutaneously could reduce the level of IL-10 markedly. TACI-Ig administration had no significant effect on the level of IFN-γin model mice.
8. Effect of TACI-Ig on splenic T, B lymphocyte subsets
The percentage of total B cells (CD19~+), activated B cells (CD19~+CD21~+, CD19~+CD23~+) and mature B cells (CD19~+IgD~+) in spleen elevated significantly in model group compared with control group except immature B cells (CD19~+IgM~+) and memory B cells (CD19~+CD27~+). Mice treated with TACI-Ig (3.75, 7.5, 15mg·kg~(-1)) subcutaneously could decrease the percentage of total B cells, activated B cells, mature B cells and immature B cells, but with no significant effect on memory B cells.
The percentage of T cell subsets in model group had no significant differences compared with control group. TACI-Ig (15mg·kg~(-1)) subcutaneously could elevate the percentage of activated Th cells (CD4~+CD25~+), but had no significant effect on other subsets of Th cells.
CONCLUSIONS
1. TACI-Ig subcutaneously had a therapeutic effect on SLE-like mouse model induced by active chromatin. It could improve renal function effectively, reduce the level of urine protein, ameliorate the pathological changes such as interstitial nephritis and spleen hyperplasia of model mice obviously.
2. TACI-Ig subcutaneously could decrease the percentage of total B cells, activated B cells and mature B cells effectively and reduce the elevated levels of autoantibodies and inflammatory cytokines evidently, which prompt that its mechanism may be related with the regulation of immune function.
引文
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