Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus.
Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus.
复制标题
DOI：
10.4049/jimmunol.0901773
复制
发表时间：
2009-11-15
期刊：
影响因子：
--
通讯作者：
Datta SK
中科院分区：
文献类型：
--
作者：
Zhang L;Bertucci AM;Ramsey-Goldman R;Burt RK;Datta SK
与常规药物治疗相比，自体造血干细胞移植（HSCT）3可以诱导难治性狼疮患者的长期缓解。在此，我们表明，在移植后患者中，CD 4 + CD 25 highFoxP 3+和一个不寻常的CD 8 + FoxP 3 + Treg亚群恢复到正常受试者的水平;伴随着几乎完全抑制致病性T细胞对核小体中组蛋白的关键肽自身表位的反应，这是凋亡细胞的主要狼疮自身抗原。除了FoxP 3的稳定持续升高之外，与通过一次活化相同处理并在短期培养中静止的移植前CD 8 T细胞相比，移植后CD 8 T细胞还维持了显著更高的CD 103、CD 103、PD-1、PD-L1和CTLA-4的表达水平。移植后的CD 8 Treg细胞具有自身抗原特异性和非特异性抑制活性，其是接触非依赖性的，主要是TGF-β依赖性的。相比之下，移植前的CD 8 T细胞具有辅助活性，这是细胞接触依赖性的。尽管已知CD 4 + CD 25高Treg细胞在常规药物治疗的狼疮的临床“缓解”期间返回，但移植后患者的CD 8 Treg显著更有效，并且它们在药物治疗的患者中不存在，其中CD 4 T细胞对核小体表位的自身反应性甚至在“临床缓解”期间持续。因此，与传统药物治疗不同，HSCT产生了新分化的LAPhigCD 103 high CD 8 TGF-β Treg细胞群，修复了人类狼疮中的Treg缺陷，使患者保持真正的免疫缓解。
Compared to conventional drug therapy, autologous hematopoietic stem cell transplantation (HSCT) 3 can induce very long-term remission in refractory lupus patients. Herein, we show that in post-transplant patients, both CD4+CD25highFoxP3+, and an unusual CD8+FoxP3+ Treg subset return to levels seen in normal subjects; accompanied by almost complete inhibition of pathogenic T cell response to critical peptide autoepitopes from histones in nucleosomes, the major lupus autoantigen from apoptotic cells. In addition to a stably sustained elevation of FoxP3, post-transplant CD8 T cells also maintained markedly higher expression levels of LAP, CD103, PD-1, PD-L1 and CTLA-4, as compared to pre-transplant CD8 T cells that were identically treated by a one-time activation and rest in short-term culture. The post-transplant CD8 Treg cells have autoantigen-specific and nonspecific suppressive activity, which is contact-independent and predominantly TGF-β-dependent. By contrast, the pre-transplant CD8 T cells have helper activity, which is cell-contact dependent. Although CD4+CD25high Treg cells are known to return during clinical “remission” of conventional drug treated lupus, the post-transplant patient's CD8 Treg are considerably more potent, and they are absent in drug treated patients in whom CD4 T cell autoreactivity to nucleosomal epitopes persists even during “clinical remission”. Therefore, unlike conventional drug therapy, HSCT generates a newly differentiated population of LAPhighCD103high CD8TGF-β Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.
登录
查看更多内容
DOI：
10.1084/jem.20021387
发表时间：
2003-02-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Barthlott T;Kassiotis G;Stockinger B
通讯作者：
Stockinger B
影响因子：
15.9
作者：
BALASHOV, KE;KHOURY, SJ;WEINER, HL
通讯作者：
WEINER, HL
DOI：
10.1111/j.1749-6632.2003.tb06035.x
发表时间：
2003-01-01
期刊：
IMMUNE MECHANISMS AND DISEASE
影响因子：
--
作者：
Datta, SK
通讯作者：
Datta, SK
SLE-全身性红斑狼疮的造血干细胞移植。
影响因子：
4.9
作者：
Burt, RK;Traynor, AE
通讯作者：
Traynor, AE
DOI：
10.1073/pnas.101123098
发表时间：
2001-05-22
影响因子：
11.1
作者：
Jiang, H;Braunstein, NS;Chess, L
通讯作者：
Chess, L