IL-10修饰的未成熟树突状细胞与CTLA-4Ig联合应用对狼疮鼠干预作用的研究
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摘要
目的：初步探讨IL-10修饰的未成熟树突状细胞与CTLA-4Ig联合应用对狼疮鼠的影响及其机制,为免疫疫苗治疗SLE的进一步研究打下基础。方法：1、IL-10修饰的狼疮小鼠骨髓源性imDC培养：无菌提取小鼠股骨及胫骨骨髓细胞进行体外原代培养。在培养至第5d时将实验分为4组：(1)6-DC组：继续培养至第6d；(2)9-DC组：继续培养至第9d；(3)6-IL-10-DC组：于第5d换液时加入IL-10继续培养至第6d；(4)9-IL-10-DC组：于第5d换液时加入IL-10,以后仍隔天换液并每次均加入IL-10,培养至第9d。倒置显微镜下观察细胞形态和数量的变化。流式细胞仪鉴定细胞的纯度和成熟度(CD11c为小鼠DC表面的特异性标志,因此用其鉴定细胞及其纯度,CD80、CD86及MCHⅡ则随着其成熟而增多。)2、IL-10修饰的imDC与CTLA-4Ig联合应用对同系狼疮鼠的作用：选取4个月大小雌性B6.MRL-Faslpr/J狼疮小鼠30只,随机分为4组,V1-V3组每组7只,V4组9只。V1组：静脉注射6-IL-10-imDC;V2组：静脉注射6-IL-10-imDC+CTLA-4Ig；V3组：静脉注射CTLA-4Ig;V4组：静脉注射等体积PBS即安慰剂对照组；V5组：选取6只4个月大小的雌性C57BL/6J小鼠：仅在相同条件下饲养而未予任何干预,即为正常对照组。检测各组小鼠24h尿蛋白、血清中ANA和抗dsDNA抗体的含量、血清中IL-17A的含量及脾脏中Th17细胞和Treg细胞的比例,比较各组的差异。结果：1、在培养的细胞中,应用流式细胞仪检测显示DCs的表面标志CD11c的阳性率达89.2%,即所培养的DCs的纯度达89.2%。而6-IL-10-DC表达MCHⅡ、CD40、CD86、CD80最低,9-CD表达MCHⅡ、CD86、CD80、CD40最高。其中6-DC与9-IL-10-DC差异无统计学意义(P>0.05),其余各组差异均具有统计学意义(均P<0.05)。2、干预前V1、V2、V3、V4组24h尿蛋白、血清中的ANA、抗ds-DNA抗体比较差异无统计学意义(均P>0.05),均高于V5组,差异有统计学意义(均P<0.05)。3、末次干预2W后V1、V2、V3组的24小时尿蛋白、血清ANA及抗ds-DNA均较干预前下降,差异均有统计学意义(均P<0.05),而V5组观察开始与结束时以上指标差异均无统计学意义(均P>0.05),V4组干预后24h尿蛋白较前升高,差异有统计学意义(P<0.05),而其血清ANA及血清抗ds-DNA抗体干预前后差异均无统计学意义(均P>0.05)。4、末次干预2W后,各组24h尿蛋白定量由低到高依次为V5组(758.67±357.20)μg、V2组(788.29±114.44)μg、V3组(1036.86±155.14)μg、V1组(1059.43±141.57)μg、V4组的(1692±252.60)μg。以上各组24h尿蛋白比较差异有统计学意义(F=23.738,P=0.000),两两比较发现V1组与V3组、V2组与V5组差异无统计学意义(均P>0.05),其余组间差异均有统计学意义(均P<0.05)。血清ANA抗体水平V1组为(10.36±1.68)pg/ml、V3组为(10.10±1.42)pg/ml、V2组为(9.95±0.98)pg/ml,V1-V3组均较V4组的(13.37±2.95)pg/ml低,但高于V5组的(7.65±1.82)pg/ml,以上各组ANA抗体比较差异有统计学意义(F=8.090,P<0.001),但其中V1组与V2、V3组,V2组与V3组差异均无统计学意义(均P>0.05),其余组间差异有统计学意义(均P<0.05)。血清抗ds-DNA抗体水平V1组为(17.716±1.89)IU/ml、V3组为(17.34±2.37)IU/ml,高于V2组的(13.11±2.10)IU/ml,V1-V3组均较V4组的(23.61±4.71)IU/ml低,但高于V5组的(11.24±1.53)IU/ml,以上各组抗ds-DNA抗体水平比较差异有统计学意义(X2=23.994,P<0.001),SNK两两比较发现V1组与V3,V2与V5差异均无统计学意义(均P>0.05),而其余组间差异均有统计学意义(均P<0.05)。5、末次干预2W后血清中IL-17A的浓度V3组为(176.61±27.61)pg/ml,V1组的为(174.57±25.39)pg/ml,均高于V2组的(139±0.98)pg/ml,但V1-V3组的均较V4组的(300.53±84.09)pg/ml低,而较V5组的(118.80±30.35)pg/ml高,以上各组血清中IL-17A的浓度比较差异有统计学意义(X2=26.415,P<0.001),其中SNK两两比较示V1组与V3,V2与V5差异均无统计学意义(均P>0.05),而其余组间差异均有统计学意义(均P<0.05),包括V4组较V5组明显升高。Vl组的脾脏淋巴细胞Th17细胞的比例为(2.20±0.47)%、V3组的为(2.12±0.47)%,均高于V2组的(1.64±0.30)%,V1-V3组均低于V4组的(3.483±1.01)%,较V5组的(1.01±0.49)%的高,以上各组脾脏淋巴细胞Th17细胞的比例的浓度比较差异有统计学意义(X2=23.177,P<0.001),其中SNK两两比较示V1组与V3,V2与V5差异均无统计学意义(均P>0.05),而其余组间差异均有统计学意义(均P<0.05),包括V4组较V5组明显升高。6、V4组狼疮小鼠的脾脏Th17细胞的比例与血清中的IL-17A、ds-DNA抗体及24h尿蛋白呈正相关,与血清中的ANA无相关；血清中的IL-17A含量与抗ds-DNA及24h尿蛋白呈正相关,与血清中的ANA无相关。7、末次干预2W后脾脏淋巴细胞Treg细胞的比例V2组为(6.39±0.87)%,高于V1组的(3.70±1.02)%及V3组的(3.55±1.12)%,V1-V3组均高于V4组的(1.88±0.69)%,均低于V5组的(10.95±1.85)%。以上各组脾脏淋巴细胞Treg细胞的比例比较差异有统计学意义(F=67.065,P<0.001),其中V1组与V3组差异无统计学意义(P>0.05),其余组间差异均有统计学意义(均P<0.05)。结论：IL-10修饰的imDC、CTLA4-Ig或IL-10修饰的imDC与CTLA4-Ig联合应用输入同基因狼疮鼠体内,均可以诱导其产生免疫耐受,能使狼疮鼠血清ANA抗体、ds-DNA抗体及24h尿蛋白明显下降。且联合应用对于狼疮鼠的干预效果优于两者单独应用。下调Th17细胞及其主要细胞因子IL-17A的水平、上调Treg细胞的表达可能是IL-10修饰的imDC.CTLA4-Ig或两者联合应用对B6.MRL-Faslpr/J狼疮小鼠干预作用的重要免疫学机制之一。血清中的IL-17A水平有可能会成为判断SLE病情严重程度和疗效的新指标。
Objective:To investigate effects and the mechanism of interleukin-10-treated immature dendritic cells unite CTLA4-Ig on lupus-prone B6.MRL-Faslpr/J mice.To explore new methods of immuneization to treat SLE.Methods:1.To culture interleukin-10-treated immature dendritic cells of upus-prone mice:With erythrocyte lysis buffer of mice,we extracted precursors of dendritic cells from mice bone marrow. We started cell primary culture by induction of cytokines. At the fifth day of the culture, the experiment was divided into four groups:(1)the sixth day-DC:Continue to culture to the sixth day;(2)the nith day-DC:Continue to culture to the ninth day;(3)the sixth day IL-10-treated-DC:medium was changed on5th day of IL-10,and cultuerd to sixth day;(4)the ninth day IL-10-treated-DC:medium was changed on5th day of IL-10, and later still the next day the medium was changed and each of IL-10, cultured to ninth day.We compared differences in morphology and phenotype among the four groups.2. Effects of interleukin-10-treated immature dendritic cells unite CTLA4-Ig on lupus-prone B6. MRL-Faslpr/J mice:select30four mouths old female lupus-prone B6.MRL-Faslpr/J mice, trials were divided into four groups, V1～V3group:seven per group,V4was nine.V1group:injected6-IL-10-imDC though tail vein;V2group:injected6-IL-10-imDC+CTLA-4Ig though tail vein;V3group:injected CTLA-4Ig though tail vein;V4group:intravenous injection of equal volume of PBS naming placebo control group.V5group: select six four moths old female C57BL/6J mice only reared under the same conditions has not been any interventionas called normal control group. Detecting each group's concentration of IL-17A, ANA and anti-ds-DNA antibody in the mice's serum and the mice's24h urine protein and the percentage of Th17,Treg cells in homogenate of spleens and compare the differences of each group.Results:1. In cultured cells, detected by flow cytometry of DCs surface markers CD11c positive rate of89.2%, the purity of the cultured DCs was89.2%.6-IL-10-to-DC expressed MCHⅡ, CD40, CD86, CD80were lowest,and the expression of MCHⅡ, CD86, CD80, CD40in9-CD were highest. Difference was all statistically significant (all P<0.05).2.Before the intervention, the mice's24h urine protein and the concentration of IL-17A,ANA and anti-ds-DNA antibody in the mice's serum were all not significantly statistic difference between V1-V4group(all P>0.05),and they were all hight than V5group,the difference was statistically significant(all P<0.05). 3. After two weeks of the last intervention,V1and V2,V3group,the24-hour urine protein and the concentration of serum's ANA and anti-ds-DNA antibody compared with before intervention all decreased, the difference were all statistically significant(all P<0.05).The difference of the above indexs of V5group before and after the observation were all not statistically significant(all P>0.05).After intervention,V4group's24-hour urine protein increased,the difference was statistically significant(P<0.05), serum's ANA and anti-ds-DNA antibody before and after the intervention were all not significant difference(all P>0.05).4. After two weeks of the last intervention,each groups24h urinary protein from low to high followed by:V5group which was(758.67±357.20)μg,V2group which was(788.29±114.44)μg,the V3group was (1036.86±155.14) μg,the V1group was(1059.43±141.57)μg and theV4group which was (1692±252.60) μg, each group24h urinary urine protein were statistically significant different (F=23.738,P<0.001),where V1group V3group differences were not statistically significant(P>0.05),among other groups were all statistically significant(all P<0.05). The ANA antibody of the V1group was (10.36±1.68) pg/ml and V3group was (10.10±1.42) pg/ml and V2group was (9.95±0.98) pg/ml, they were all lower than V4group which was (13.37±2.95) pg/ml and higher than V5group (7.65±1.82) pg/ml.The difference of the ANA antibodies of the above groups were statistically significant.(F=8.090,P=0.000), of which the V1and V2, V3, V2group and the V3group were all not statistically significant differences(all P>0.05),and among other groups were all statistically significant(all P<0.05).The anti-ds-DNA antibody of the V1group was (17.716±1.89) IU/ml and the V3group was (17.34±2.37) IU/ml, higher than the V2group which was (13.11±2.10) IU/ml,V1-V3groups's were all lower than V4 group which was (23.61±4.71) IU/ml and all higher than and V5group which was (11.24±1.53) IU/ml.The difference of the anti-ds-DNA antibodies of the above groups were statistically significant (X2=23.994,P<0.001),which use SNK two two comparison show that V1group and the V3group, V2and V5were all not statistically significant differences (all P>0.05), and among other groups were all statistically significant differences (all P<0.05).5. After two weeks of the last intervention,the IL-17A of the V3group was(176.61±27.61)pg/ml and the V1group was(174.57±25.39)pg/ml, higher than the V2group which was(139±0.98)pg/ml, V1-V3groups's were all lower than V4group which was (300.53±84.09)pg/ml and all higher than and V5group which was (118.80±30.35) pg/ml.The difference of IL-17A of the above groups were statistically significant differences (X2=26.415,P<0.001), which used SNK two two comparison showed that V1group and the V3group, V2and V5were all not statistically significant differences(all P>0.05), and among other groups were all statistically significant differences (all P<0.05), including the V4group were significantly higher than V5group. The percentage of Th17cells in homogenate of spleens of the V1group was(2.20±0.47)%and V3group was(2.12±0.47)%,higher than the V2group (1.64±0.30)%,and V1-V3groups‘s were all lower than V4group which was (3.483±1.01)%and higher than V5group which was(1.01±0.49)%.The difference of the percentage of Th17cells in homogenate of spleens of the above groups were statistically significant differences(X2=23.177,P<0.001),which used SNK two two comparison showed that V1group and the V3group, V2and V5were all not statistically significant differences(all P>0.05), and among other groups were all statistically significant differences(all P<0.05), including the V4group were significantly higher than V5group. 6. The percentage of Th17cells in homogenate of spleens of V4group's lupus-prone B6.Fas mice was positively correlated with IL-17A and anti-ds-DNA antibody in serum and the24h urine protein,however it was not correlated with ANA in serum, And IL-17A in serum which is the main secrete factor of Th17cells was also positively correlated with anti-ds-DNA antibody in serum and the24h urine protein, and it was also not correlated with ANA in serum.7. After two weeks of the last intervention,the percentage of Treg cells in homogenate of spleens of the V2group was(6.39±0.87)%, higher than the VI group which was(3.70±1.02)%and V3group which was(3.55±1.12)%and each of the V1～V3group's was higher than V4group which was(1.88±0.69)%and was lower than V5group which was(10.95±1.85)%.The percentage of Treg cells in homogenate of spleens were statistically significant different (F=67.065, P<0.001), where V1group V3group's difference was not statistically significant(P>0.05),and among other groups were all statistically significant(all P
Objective:To investigate effects and the mechanism of interleukin-10-treated immature dendritic cells unite CTLA4-Ig on lupus-prone B6.MRL-Faslpr/J mice.To explore new methods of immuneization to treat SLE.Methods:1.To culture interleukin-10-treated immature dendritic cells of upus-prone mice:With erythrocyte lysis buffer of mice,we extracted precursors of dendritic cells from mice bone marrow. We started cell primary culture by induction of cytokines. At the fifth day of the culture, the experiment was divided into four groups:(1)the sixth day-DC:Continue to culture to the sixth day;(2)the nith day-DC:Continue to culture to the ninth day;(3)the sixth day IL-10-treated-DC:medium was changed on5th day of IL-10,and cultuerd to sixth day;(4)the ninth day IL-10-treated-DC:medium was changed on5th day of IL-10, and later still the next day the medium was changed and each of IL-10, cultured to ninth day.We compared differences in morphology and phenotype among the four groups.2. Effects of interleukin-10-treated immature dendritic cells unite CTLA4-Ig on lupus-prone B6. MRL-Faslpr/J mice:select30four mouths old female lupus-prone B6.MRL-Faslpr/J mice, trials were divided into four groups, V1～V3group:seven per group,V4was nine.V1group:injected6-IL-10-imDC though tail vein;V2group:injected6-IL-10-imDC+CTLA-4Ig though tail vein;V3group:injected CTLA-4Ig though tail vein;V4group:intravenous injection of equal volume of PBS naming placebo control group.V5group: select six four moths old female C57BL/6J mice only reared under the same conditions has not been any interventionas called normal control group. Detecting each group's concentration of IL-17A, ANA and anti-ds-DNA antibody in the mice's serum and the mice's24h urine protein and the percentage of Th17,Treg cells in homogenate of spleens and compare the differences of each group.Results:1. In cultured cells, detected by flow cytometry of DCs surface markers CD11c positive rate of89.2%, the purity of the cultured DCs was89.2%.6-IL-10-to-DC expressed MCHⅡ, CD40, CD86, CD80were lowest,and the expression of MCHⅡ, CD86, CD80, CD40in9-CD were highest. Difference was all statistically significant (all P<0.05).2.Before the intervention, the mice's24h urine protein and the concentration of IL-17A,ANA and anti-ds-DNA antibody in the mice's serum were all not significantly statistic difference between V1-V4group(all P>0.05),and they were all hight than V5group,the difference was statistically significant(all P<0.05). 3. After two weeks of the last intervention,V1and V2,V3group,the24-hour urine protein and the concentration of serum's ANA and anti-ds-DNA antibody compared with before intervention all decreased, the difference were all statistically significant(all P<0.05).The difference of the above indexs of V5group before and after the observation were all not statistically significant(all P>0.05).After intervention,V4group's24-hour urine protein increased,the difference was statistically significant(P<0.05), serum's ANA and anti-ds-DNA antibody before and after the intervention were all not significant difference(all P>0.05).4. After two weeks of the last intervention,each groups24h urinary protein from low to high followed by:V5group which was(758.67±357.20)μg,V2group which was(788.29±114.44)μg,the V3group was (1036.86±155.14) μg,the V1group was(1059.43±141.57)μg and theV4group which was (1692±252.60) μg, each group24h urinary urine protein were statistically significant different (F=23.738,P<0.001),where V1group V3group differences were not statistically significant(P>0.05),among other groups were all statistically significant(all P<0.05). The ANA antibody of the V1group was (10.36±1.68) pg/ml and V3group was (10.10±1.42) pg/ml and V2group was (9.95±0.98) pg/ml, they were all lower than V4group which was (13.37±2.95) pg/ml and higher than V5group (7.65±1.82) pg/ml.The difference of the ANA antibodies of the above groups were statistically significant.(F=8.090,P=0.000), of which the V1and V2, V3, V2group and the V3group were all not statistically significant differences(all P>0.05),and among other groups were all statistically significant(all P<0.05).The anti-ds-DNA antibody of the V1group was (17.716±1.89) IU/ml and the V3group was (17.34±2.37) IU/ml, higher than the V2group which was (13.11±2.10) IU/ml,V1-V3groups's were all lower than V4 group which was (23.61±4.71) IU/ml and all higher than and V5group which was (11.24±1.53) IU/ml.The difference of the anti-ds-DNA antibodies of the above groups were statistically significant (X2=23.994,P<0.001),which use SNK two two comparison show that V1group and the V3group, V2and V5were all not statistically significant differences (all P>0.05), and among other groups were all statistically significant differences (all P<0.05).5. After two weeks of the last intervention,the IL-17A of the V3group was(176.61±27.61)pg/ml and the V1group was(174.57±25.39)pg/ml, higher than the V2group which was(139±0.98)pg/ml, V1-V3groups's were all lower than V4group which was (300.53±84.09)pg/ml and all higher than and V5group which was (118.80±30.35) pg/ml.The difference of IL-17A of the above groups were statistically significant differences (X2=26.415,P<0.001), which used SNK two two comparison showed that V1group and the V3group, V2and V5were all not statistically significant differences(all P>0.05), and among other groups were all statistically significant differences (all P<0.05), including the V4group were significantly higher than V5group. The percentage of Th17cells in homogenate of spleens of the V1group was(2.20±0.47)%and V3group was(2.12±0.47)%,higher than the V2group (1.64±0.30)%,and V1-V3groups‘s were all lower than V4group which was (3.483±1.01)%and higher than V5group which was(1.01±0.49)%.The difference of the percentage of Th17cells in homogenate of spleens of the above groups were statistically significant differences(X2=23.177,P<0.001),which used SNK two two comparison showed that V1group and the V3group, V2and V5were all not statistically significant differences(all P>0.05), and among other groups were all statistically significant differences(all P<0.05), including the V4group were significantly higher than V5group. 6. The percentage of Th17cells in homogenate of spleens of V4group's lupus-prone B6.Fas mice was positively correlated with IL-17A and anti-ds-DNA antibody in serum and the24h urine protein,however it was not correlated with ANA in serum, And IL-17A in serum which is the main secrete factor of Th17cells was also positively correlated with anti-ds-DNA antibody in serum and the24h urine protein, and it was also not correlated with ANA in serum.7. After two weeks of the last intervention,the percentage of Treg cells in homogenate of spleens of the V2group was(6.39±0.87)%, higher than the VI group which was(3.70±1.02)%and V3group which was(3.55±1.12)%and each of the V1～V3group's was higher than V4group which was(1.88±0.69)%and was lower than V5group which was(10.95±1.85)%.The percentage of Treg cells in homogenate of spleens were statistically significant different (F=67.065, P<0.001), where V1group V3group's difference was not statistically significant(P>0.05),and among other groups were all statistically significant(all P
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13. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol,2005, 6(11):1133-1141.
14. Santiago-Raber ML, Laporte C, Reininger L, et al., Genetic basis of murine lupus. Autoimmun Rev,2004,3(1):33-39.
15. Fujino S, Andoh A, Bamba S, et al.Increased expression of interleukin 17 in inflammatory bowel disease. Gut,2003,52(1):65-70.
16. Hwang SY, Kim HY. Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells, 2005,19(2):180-184.
17.于周,吕志宇,李作孝.35例多发性硬化患者Th17细胞及相关细胞因子的检测.重庆医学,2011,7(40)：644-649.
18. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus:implications for Th 17-mediated inflammation in auto-immunity. Clin Immunol, 2008,127(3):385-393.
19. Yang J, Chu Y, Yang X, et al., Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum,2009,60(5): 1472-1483.
20. Hsu HC, Yang P, Wang J, et al.Interleukin 17-producing T helper cells
and interleukin 17orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol,2008,9(2):166-175.
21. Zhang Z, Kyttaris VC, Tsokos GC.The role of IL-23/IL-17 axis in lupus nephritis. J Immunol,2009,183(5):3160-3169.
22. Kyttaris VC, Zhang Z, Kuchroo VK, et al.Cutting edge:IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-1pr/1pr mice. J Immunol,2010,184(9):4605-4609.
23. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alphachains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol,1995,155(3):1151-1164.
24. Fontenot JD, Gavin MA, Rudensky AY, et al. Foxp3 programs the development and function of CD4+CD25+regulatory T cells. Nat Immunol,2003,4(4):330-336.
25. Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients withprimary biliary cirrhosis:the serum cytokine profile and peripheral cell population. Clin Exp Immunol, 2009,156(2):217-225。
26. Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum, 2009,60(5):1472-1483.
27. Liu MF, Wang CR, Fung LL, et al. Decreased CD4+CD25+T cells in peripheral blood of patients with systemic lupus erythematosus.Scand J Immunol,2004,59(2):198-202.
28. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus.J Autoimmun,
2003,21(3):273-276.
29. Mellor-Pita S, Citores MJ, Castejon R, et al.Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis,2006,65(4):553-554.
30.马纪林,蔡龙,施华萍,等.系统性红斑狼疮患者外周血CD4+CD25+FOXP3+调节性T细胞的检测和意义.中华风湿病学杂志,2007,11(11)：654-657.
31.朱珠,林有坤,林发全,等.CD4+CD25+T细胞和NK细胞与SLE病情活动相关性的研究.中国麻风皮肤病杂志,2008,24(2)：99-101.
32.刘京平,林有坤,何钠.首诊系统性红斑狼疮住院患者ANA、抗ds-DNA与病情活动的研究,中国皮肤性病学杂志,2008,22(1),26-28.
33. Steinman RM, Cohn ZA. Identification of a novel cell type in peritheral lymphoid organs of mice. I. Morphology,quantitation, tissue distribution. J Exp Med,1973,137(5):1142-1162.
34. Cella M, Sallusto F, Lanzavecchia A. Origin,maturation and antigen presenting function of dendritic cells. Curr Opin Immunol,1997,9:10-16.
35. Thomas R, Davis LS, Lipsky PE.Isolation and characterization of human peripheral blood dendritic cells.J Immunol,1993,150(3):821-834.
36.O'Doherty U, Steinman RM, Peng M,e tal.Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-condition edmedium. J Exp Med,1993,178(3):1067-1076.
37. McLellan AD, Starling GC, Williams LA, e tal.Activation of human peripheral blood dendritic cells induces the CD86 costimulatory molecule. Eur J Immunol,1995,25(7):2064-2068.
38. McLellan AD, Sorg RV, Williams LA, e tal.Human dendritic cells
activate T lymphocytes via a CD40:CD40 liganddependent pathway. Eur J Immunol,1996,26(6):1204-1206.
39. Wallet MA, Sen P, Tisch R.Immunoregulation of dendritic cells. Clin Med Res,2005,3(3):166-175.
40. Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997; 15 9:4772-4780.
41. Steinbrink K, Jonuleit H, Muller G,e tal. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood,1999,93:1634-1642.
42. Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res,2003,63:2150-2157.
43. Haase C, Jorgensen TN, Michelsen BK. Both exogenous and endogenou-s interleukin-10 affects the maturation of bone-marrow-derived dendritic cells in vitroand strongly influences T-cell priming in vivo. Immunology, 2002,107:489-499.
44. Manavalan JS, Rossi PC, Vlad G, e tal. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Imm-unol,2003,11:245-258.
45. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol,2000,18:767-811.
46. Linsley P,Nadler SG.The clinical utility of inhibiting CD28-mediated costimulation.ImmunolRev,2009,229(1):307-321.
47. Salazar L, Aravena O, Contreras-Levicoy J, e tal.Short-term lipopolysac-charide stimulation induces differentiation of murine bone marrow-deri-
ved dendritic cells into a tolerogenic phenotype.Eur Cytokine Netw,2007 Jun;18(2):78-85.
48. Buckland M, Lombardi G. Aspirin and the induction of tolerance by dendritic cells. Handb Exp Pharmaco1,2009,(188):197-213.
49.韩波,胡燕华.CTLA4-Ig基因修饰的树突状细胞抑制角膜移植排斥反应的机制研究.眼科研究,2007,25(5)：347-350.
50.应林燕,符州,罗健,等.CTLA4-Ig基因修饰的树突状细胞体外对Thl/Th2平衡的影响.细胞与分子免疫学杂志,2011,27(3)：266-269.
51. Ko HJ, Cho ML, Lee SY, e tal.CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Fox-p3+ regulatory T cell population.J Autoimmun,2010,34(2):111-120.
1. Yazdany J, Davis J. The role of CD40 ligand in systemic lupus erythematosus. Lupus,2004,13(5):377-380.
2. Wang X, Huang W, Schiffer LE, Mihara M, e tal.Effects of anti-CD 154 treatment on B cells in systemic lupus erythematosus. Arthritis Rheum,2003,48(2):495-506.
3. Bono L, Cameron JS, Hicks JA. The very long-term prognosis and com-plications of lupus nephritis and its treatmen t.QJM,1999,92:211-218.
4. Davis JC Jr, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D. Phase I clinical trial of a monoclonal antibody against CD40-ligand(IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001, 28:95-101.
5. Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus.200 4,13(5):391-397.
6. Brunet JF,Denizot F,Luciani MF,et alo.A new member of the immun-oglobulin superfamily-CTLA4.Nature,1987,328(6127):267-275.
7.汪厚平,马宝骊,韩子英,等.CTLA4-Ig诱导细胞无能的作用机制探讨.上海免疫学杂志,2000,20(3)：155-158.
8. June CH,Bluestone JA,Nadler LM,et al.The B7 and CD28 receptor families.Immunol Today,1994,15:321-331.
9. Finek D. BK, Linsley PS, Wofsy Treatment of murine lupus with CTLA4Ig.Science,1994,265(5175):1225-1227。
10.Sfikakis PP, Via CS. Expression of CD28,CTLA4,CD80,and CD86 molec-ules in patients with autoimmune rheumatic diseases:implications for im-munotherapy. Clin Immunol Immunopathol.1997 Jun,83(3):195-198.
11.Zheng Y, Gallucci S, Gaughan JP,e tal. A role for B cell-activating factor of the TNF family in chemically induced autoimmunity. J Immunol, 2005,175(9):6163-6168.
12.Schneider P, MacKay F, Steiner V, e tal. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999,189(11):1747-1756.
13.吴梅,赵传靖.生物制剂治疗系统性红斑狼疮的研究进展.中国麻风皮肤病杂志,2005,21(10)：799-802.
14.穆荣,藏振鹏,粟占国等.T细胞疫苗治疗系统性红斑狼疮的初步临床研究.中华内科杂志,2004,43(8)；568-571.
15.Steinman RM, Cohn ZA. Identification of a novel cell type in peritheral lymphoid organs of mice. I. Morphology, quantitation,tissue distribution. J Exp Med,1973,137(5):1142-1162.
16.Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol,1997,9:10-16.
17.Thomas R, Davis LS, Lipsky PE. Isolation and characterization of human peripheral blood dendritic cells.J Immunol,1993,150(3):821-834.
18.O'Doherty U, Steinman RM, Peng M, e tal. Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-condition edmedium. J Exp Med.1993,178(3):1067-1076.
19.McLellan AD, Starling GC, Williams LA, Hock BD, Hart DNJ: Activation of human peripheral blood dendritic cells induces the CD86 costimulatory molecule. Eur J Immunol,1995,25(7):2064-2068.
20.McLellan AD, Sorg RV, Williams LA, e tal.Human dendritic cells activate T lymphocytes via a CD40:CD40 liganddependent pathway. Eur J Immunol,1996,26(6):1204-1206.
21.谢君,负载自身抗原的未成熟树突状细胞诱导狼疮鼠免疫耐受的研究[学位论文],广西,广西医科大学,2009.
22.Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressingIL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol,1995,155(3):1151-1164.
23.Fontenot JD, Gavin MA, Rudensky AY, et al.Foxp3 programs the development and function of CD4+CD25+regu-latory T cells. Nat Immunol,2003,4(4):330-336.
24.Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients withprimary biliary cirrhosis:the serum cytokine profile and peripheral cell population. Clin Exp Immunol,
2009,156(2):217-225.
25.Hori S, Nomura T, Sakaguchi S. Control of Regulatory T Cell Develop-ment by the Transcription Factor Foxp3. Science,2003:299(5609) 1057-1061.
26.Roncarolo MG, Gregori S, Battaglia M, e tal. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev,2006 Aug,212:28-50.
27.Tang Q, Bluestone JA, Regulatory T-cell physiology and application to treat auto immunity. Immunol Rev,2006,212:217-237.
28.Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut,2003,52(1):65-70.
29.Hwang SY, Kim HY.Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells,2005,19(2): 180-184.
30.于周,吕志宇,李作孝.5例多发性硬化患者Thl7细胞及相关细胞因子的检测.重庆医学,2011,(40)7：644-649.
31. Kyttaris VC, Zhang Z, Kuchroo VK, et al.Cutting edge:IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol,2010,184(9):4605-4609.
32. Anolin JH, Barnard J, Cappione A, et al. Rituximab improves peripheral B cell abnormalities in human Systemic lupus erythematosus. Arthritis Rheum,2004,50(1):3580-3590.
33.Domer T, Kaufmann J, Wegener WA, et al. Initial clinical trial of
epratuzumab (humanized anti-CD22 antibody)for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther,2006,8(3):R74.
2. Steinman RM. Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med,2007,13 (10):1155-1159.
3. Adema GJ.Dendritic cells from bench to bedside and back. Immunol Lett,2009,122:128-130.
4. Morel PA, Feili-Hariri M, Coates PT, et al. Dendritic cells, T cell tolerance and therapy of adverse immune reactions. Clin Exp Immunol,2003,133:1-10.
5. Mami NB, Mohty M, Aurran-Schleinitz T, et al. Blood dendritic cells in patients with chronic lymphocytic leukaemia. Immunobiology, 2008,213:493-498.
6. Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol,2007,7:610-621.
7. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell.IV.Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J ExpMed,1989,170(6):2081-2095.
8. Hawiger D, Inaba K. Dendritic cells induce peripheral T cell unresponsiveness under steady conditions in vivo. J Exp Me-d,2001,194(6):769-779.
9. Brunet JF,Denizot F,Luciani MF,et al. A new member of the immunoglo-bulin superfamily-CTLA4.Nature,1987,328(6127):267-275.
10.汪厚平,马宝骊,韩子英,等.CTLA4-Ig诱导细胞无能的作用机制探讨.
上海免疫学杂志,2000,20(3)：155-158.
11. June CH,Bluestone JA,Nadler LM,et al.The B7 and CD28 receptor families.Immunol Today,1994,15:321-331.
12. Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire:the Th17 lineage. Curr Opin Immunol,2006,18(3): 349-356.
13. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol,2005, 6(11):1133-1141.
14. Santiago-Raber ML, Laporte C, Reininger L, et al., Genetic basis of murine lupus. Autoimmun Rev,2004,3(1):33-39.
15. Fujino S, Andoh A, Bamba S, et al.Increased expression of interleukin 17 in inflammatory bowel disease. Gut,2003,52(1):65-70.
16. Hwang SY, Kim HY. Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells, 2005,19(2):180-184.
17.于周,吕志宇,李作孝.35例多发性硬化患者Th17细胞及相关细胞因子的检测.重庆医学,2011,7(40)：644-649.
18. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus:implications for Th 17-mediated inflammation in auto-immunity. Clin Immunol, 2008,127(3):385-393.
19. Yang J, Chu Y, Yang X, et al., Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum,2009,60(5): 1472-1483.
20. Hsu HC, Yang P, Wang J, et al.Interleukin 17-producing T helper cells
and interleukin 17orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol,2008,9(2):166-175.
21. Zhang Z, Kyttaris VC, Tsokos GC.The role of IL-23/IL-17 axis in lupus nephritis. J Immunol,2009,183(5):3160-3169.
22. Kyttaris VC, Zhang Z, Kuchroo VK, et al.Cutting edge:IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-1pr/1pr mice. J Immunol,2010,184(9):4605-4609.
23. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alphachains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol,1995,155(3):1151-1164.
24. Fontenot JD, Gavin MA, Rudensky AY, et al. Foxp3 programs the development and function of CD4+CD25+regulatory T cells. Nat Immunol,2003,4(4):330-336.
25. Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients withprimary biliary cirrhosis:the serum cytokine profile and peripheral cell population. Clin Exp Immunol, 2009,156(2):217-225。
26. Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum, 2009,60(5):1472-1483.
27. Liu MF, Wang CR, Fung LL, et al. Decreased CD4+CD25+T cells in peripheral blood of patients with systemic lupus erythematosus.Scand J Immunol,2004,59(2):198-202.
28. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus.J Autoimmun,
2003,21(3):273-276.
29. Mellor-Pita S, Citores MJ, Castejon R, et al.Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis,2006,65(4):553-554.
30.马纪林,蔡龙,施华萍,等.系统性红斑狼疮患者外周血CD4+CD25+FOXP3+调节性T细胞的检测和意义.中华风湿病学杂志,2007,11(11)：654-657.
31.朱珠,林有坤,林发全,等.CD4+CD25+T细胞和NK细胞与SLE病情活动相关性的研究.中国麻风皮肤病杂志,2008,24(2)：99-101.
32.刘京平,林有坤,何钠.首诊系统性红斑狼疮住院患者ANA、抗ds-DNA与病情活动的研究,中国皮肤性病学杂志,2008,22(1),26-28.
33. Steinman RM, Cohn ZA. Identification of a novel cell type in peritheral lymphoid organs of mice. I. Morphology,quantitation, tissue distribution. J Exp Med,1973,137(5):1142-1162.
34. Cella M, Sallusto F, Lanzavecchia A. Origin,maturation and antigen presenting function of dendritic cells. Curr Opin Immunol,1997,9:10-16.
35. Thomas R, Davis LS, Lipsky PE.Isolation and characterization of human peripheral blood dendritic cells.J Immunol,1993,150(3):821-834.
36.O'Doherty U, Steinman RM, Peng M,e tal.Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-condition edmedium. J Exp Med,1993,178(3):1067-1076.
37. McLellan AD, Starling GC, Williams LA, e tal.Activation of human peripheral blood dendritic cells induces the CD86 costimulatory molecule. Eur J Immunol,1995,25(7):2064-2068.
38. McLellan AD, Sorg RV, Williams LA, e tal.Human dendritic cells
activate T lymphocytes via a CD40:CD40 liganddependent pathway. Eur J Immunol,1996,26(6):1204-1206.
39. Wallet MA, Sen P, Tisch R.Immunoregulation of dendritic cells. Clin Med Res,2005,3(3):166-175.
40. Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997; 15 9:4772-4780.
41. Steinbrink K, Jonuleit H, Muller G,e tal. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood,1999,93:1634-1642.
42. Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res,2003,63:2150-2157.
43. Haase C, Jorgensen TN, Michelsen BK. Both exogenous and endogenou-s interleukin-10 affects the maturation of bone-marrow-derived dendritic cells in vitroand strongly influences T-cell priming in vivo. Immunology, 2002,107:489-499.
44. Manavalan JS, Rossi PC, Vlad G, e tal. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Imm-unol,2003,11:245-258.
45. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol,2000,18:767-811.
46. Linsley P,Nadler SG.The clinical utility of inhibiting CD28-mediated costimulation.ImmunolRev,2009,229(1):307-321.
47. Salazar L, Aravena O, Contreras-Levicoy J, e tal.Short-term lipopolysac-charide stimulation induces differentiation of murine bone marrow-deri-
ved dendritic cells into a tolerogenic phenotype.Eur Cytokine Netw,2007 Jun;18(2):78-85.
48. Buckland M, Lombardi G. Aspirin and the induction of tolerance by dendritic cells. Handb Exp Pharmaco1,2009,(188):197-213.
49.韩波,胡燕华.CTLA4-Ig基因修饰的树突状细胞抑制角膜移植排斥反应的机制研究.眼科研究,2007,25(5)：347-350.
50.应林燕,符州,罗健,等.CTLA4-Ig基因修饰的树突状细胞体外对Thl/Th2平衡的影响.细胞与分子免疫学杂志,2011,27(3)：266-269.
51. Ko HJ, Cho ML, Lee SY, e tal.CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Fox-p3+ regulatory T cell population.J Autoimmun,2010,34(2):111-120.
1. Yazdany J, Davis J. The role of CD40 ligand in systemic lupus erythematosus. Lupus,2004,13(5):377-380.
2. Wang X, Huang W, Schiffer LE, Mihara M, e tal.Effects of anti-CD 154 treatment on B cells in systemic lupus erythematosus. Arthritis Rheum,2003,48(2):495-506.
3. Bono L, Cameron JS, Hicks JA. The very long-term prognosis and com-plications of lupus nephritis and its treatmen t.QJM,1999,92:211-218.
4. Davis JC Jr, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D. Phase I clinical trial of a monoclonal antibody against CD40-ligand(IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001, 28:95-101.
5. Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus.200 4,13(5):391-397.
6. Brunet JF,Denizot F,Luciani MF,et alo.A new member of the immun-oglobulin superfamily-CTLA4.Nature,1987,328(6127):267-275.
7.汪厚平,马宝骊,韩子英,等.CTLA4-Ig诱导细胞无能的作用机制探讨.上海免疫学杂志,2000,20(3)：155-158.
8. June CH,Bluestone JA,Nadler LM,et al.The B7 and CD28 receptor families.Immunol Today,1994,15:321-331.
9. Finek D. BK, Linsley PS, Wofsy Treatment of murine lupus with CTLA4Ig.Science,1994,265(5175):1225-1227。
10.Sfikakis PP, Via CS. Expression of CD28,CTLA4,CD80,and CD86 molec-ules in patients with autoimmune rheumatic diseases:implications for im-munotherapy. Clin Immunol Immunopathol.1997 Jun,83(3):195-198.
11.Zheng Y, Gallucci S, Gaughan JP,e tal. A role for B cell-activating factor of the TNF family in chemically induced autoimmunity. J Immunol, 2005,175(9):6163-6168.
12.Schneider P, MacKay F, Steiner V, e tal. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999,189(11):1747-1756.
13.吴梅,赵传靖.生物制剂治疗系统性红斑狼疮的研究进展.中国麻风皮肤病杂志,2005,21(10)：799-802.
14.穆荣,藏振鹏,粟占国等.T细胞疫苗治疗系统性红斑狼疮的初步临床研究.中华内科杂志,2004,43(8)；568-571.
15.Steinman RM, Cohn ZA. Identification of a novel cell type in peritheral lymphoid organs of mice. I. Morphology, quantitation,tissue distribution. J Exp Med,1973,137(5):1142-1162.
16.Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol,1997,9:10-16.
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18.O'Doherty U, Steinman RM, Peng M, e tal. Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-condition edmedium. J Exp Med.1993,178(3):1067-1076.
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