CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus.
CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus.
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DOI：
10.4049/jimmunol.181.1.47
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Via, Charles S.
中科院分区：
文献类型：
--
作者：
Puliaev, Roman;Puliaeva, Irina;Welniak, Lisbeth A.;Ryan, Abigail E.;Haas, Mark;Murphy, William J.;Via, Charles S.
CD 40/CD 40 L信号传导促进体内B细胞和CTL应答，后者在肿瘤模型中是有益的。由于CTL也可能限制狼疮中自身反应性B细胞的扩增，我们询问激动剂CD 40 mAb是否会因B细胞刺激而加重狼疮或因CTL促进而改善狼疮。这些研究使用了狼疮的诱导模型，即亲本转化F1模型，其中DBA/2脾细胞转移到B6 D2 F1小鼠中诱导慢性狼疮样移植物抗宿主病（GVHD）。尽管DBA→F1小鼠的激动剂CD 40 mAb治疗最初加剧了B细胞扩增，但它也强烈促进了供体CD 8 T细胞植入和细胞溶解活性，使得到10天时宿主B细胞被消除，这与加速的急性GVHD一致。CD 40刺激绕过了CD 8 CTL对CD 4 T细胞帮助的需要，这可能是通过许可DC来实现的，如以下所示：a）供体CD 8 T细胞而不是CD 4 T细胞的更大初始活化; B）宿主DC的更早活化; c）宿主DC扩增是CD 8依赖性的，CD 4非依赖性的;和d）使用CD 4耗尽的纯化DBA CD 8 + T细胞诱导急性GVHD。单剂量的CD 40 mAb在12周时改善狼疮样肾病，但可能不足以持续更长时间，这与持续CD 8 CTL监测的需要一致。这些结果表明，在狼疮样CD 4 T细胞驱动的B细胞过度活跃的情况下，CTL促进是可行的和有益的，并且CD 40刺激的CTL促进特性超过B细胞刺激特性。
CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate lupus due to B cell stimulation or would improve lupus due to CTL promotion. These studies used an induced model of lupus, the parent-into-F1 model in which transfer of DBA/2 splenocytes into B6D2F1 mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA→F1 mice initially exacerbated B cell expansion, it also strongly promoted donor CD8 T cell engraftment and cytolytic activity such that by ten days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing DC as shown by: a) greater initial activation of donor CD8 T cells but not CD4 T cells; b) earlier activation of host DC; c) host DC expansion that was CD8 dependent, CD4 independent; and d) induction of acute GVHD using CD4 depleted purified DBA CD8+ T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 weeks but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL promoting properties of CD40 stimulation outweigh the B cell stimulatory properties.
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DOI：
10.1084/jem.20020223
发表时间：
2002-09-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fan GC;Singh RR
通讯作者：
Singh RR
影响因子：
6.5
作者：
GLEICHMANN, E;GLEICHMANN, H
通讯作者：
GLEICHMANN, H
影响因子：
4.3
作者：
HEATH, AW;CHANG, R;HOWARD, M
通讯作者：
HOWARD, M
DOI：
10.1073/pnas.0401351101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kozel, TR;Murphy, WJ;Lyons, CR
通讯作者：
Lyons, CR
影响因子：
15.9
作者：
Koshy, M;Berger, D;Crow, MK
通讯作者：
Crow, MK