Prevention of "Humanized" diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach.
Prevention of "Humanized" diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach.
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DOI：
10.2337/db10-1523
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发表时间：
2011-04
期刊：
影响因子：
7.7
通讯作者：
Serreze DV
中科院分区：
文献类型：
--
作者：
Niens M;Grier AE;Marron M;Kay TW;Greiner DL;Serreze DV
1型糖尿病可以通过靶向致病性CD 8 + T细胞的自身抗原特异性免疫疗法在标准NOD小鼠中得到抑制。表达人HLA-A2.1但缺乏鼠主要组织相容性复合物I类分子的NOD.β2mnull.HHD小鼠发生糖尿病，其特征在于CD 8 T细胞识别某些也在人类患者中靶向的自身抗原肽。这些包括源自胰腺β细胞蛋白胰岛素（INS 1/2 A2-10和INS 1 B5-14）和胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白（IGRP 265 -273和IGRP 228 -236）的肽。因此，NOD.β2mnull.HHD小鼠代表了用于开发潜在临床可转化干预措施以抑制致糖尿病HLA-A2.1限制性T细胞应答的模型系统。从4-6周龄开始，向NOD.β2mnull.HHD雌性小鼠静脉内注射同系脾细胞，通过交联剂乙烯碳二亚胺（ECDI）将上述四种肽的各种混合物结合到所述脾细胞上。与接受与不相关的HLA-A2.1-限制性Flu 16肽偶联的脾细胞的对照组相比，用携带INS和HRP表位的完全混合物（指定为INS/IGRP-SP）的这种细胞治疗显著抑制了NOD.β2mnull.HHD受体的糖尿病发展。随后的分析发现，携带两种ECDI偶联的IGRP而非INS肽（IGRP-SP或INS-SP）的组合的同基因脾细胞有效地抑制了NOD.β 2mull.HHD小鼠中的糖尿病发展。酶联免疫斑点（ELISPOT）分析表明，INS/IGRP-SP联合可降低NOD.β 2 mnul. HHD小鼠中HLA-A2.1限制性的IGP，但不降低INS自身反应性CD 8 + T细胞应答。这些数据支持靶向HLA-A2.1-限制性IGRP自身反应性CD 8 T细胞的细胞治疗方法作为适当的人类患者中的糖尿病干预方法的潜力。
Type 1 diabetes can be inhibited in standard NOD mice by autoantigen-specific immunotherapy targeting pathogenic CD8+ T-cells. NOD.β2mnull.HHD mice expressing human HLA-A2.1 but lacking murine major histocompatibility complex class I molecules develop diabetes characterized by CD8 T-cells recognizing certain autoantigenic peptides also targeted in human patients. These include peptides derived from the pancreatic β-cell proteins insulin (INS1/2 A2–10 and INS1 B5–14) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP265–273 and IGRP228–236). Hence, NOD.β2mnull.HHD mice represent a model system for developing potentially clinically translatable interventions for suppressing diabetogenic HLA-A2.1–restricted T-cell responses. Starting at 4–6 weeks of age, NOD.β2mnull.HHD female mice were injected intravenously with syngeneic splenocytes to which various admixtures of the four above-mentioned peptides were bound by the cross-linking agent ethylene carbodiimide (ECDI). Treatment with such cells bearing the complete cocktail of INS and IGRP epitopes (designated INS/IGRP-SPs) significantly inhibited diabetes development in NOD.β2mnull.HHD recipients compared with controls receiving splenocytes coupled with an irrelevant HLA-A2.1–restricted Flu16 peptide. Subsequent analyses found syngeneic splenocytes bearing the combination of the two ECDI-coupled IGRPs but not INS peptides (IGRP-SPs or INS-SPs) effectively inhibited diabetes development in NOD.β2mnull.HHD mice. This result was supported by enzyme-linked immunospot (ELISPOT) analyses indicating combined INS/IGRP-SPs diminished HLA-A2.1–restricted IGRP but not INS autoreactive CD8+ T-cell responses in NOD.β2mnull.HHD mice. These data support the potential of a cell therapy approach targeting HLA-A2.1–restricted IGRP autoreactive CD8 T-cells as a diabetes intervention approach in appropriate human patients.
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DOI：
10.1084/jem.20061577
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fife BT;Guleria I;Gubbels Bupp M;Eagar TN;Tang Q;Bour-Jordan H;Yagita H;Azuma M;Sayegh MH;Bluestone JA
通讯作者：
Bluestone JA
DOI：
10.1073/pnas.0508621102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Pinkse, GGM;Tysma, OHM;Roep, BO
通讯作者：
Roep, BO
影响因子：
7.7
作者：
CHRISTIANSON, SW;SHULTZ, LD;LEITER, EH
通讯作者：
LEITER, EH
影响因子：
7.7
作者：
Serreze, DV;Johnson, EA;Joyce, S
通讯作者：
Joyce, S
影响因子：
64.8
作者：
Nakayama, M;Abiru, N;Eisenbarth, GS
通讯作者：
Eisenbarth, GS