PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy.
PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy.
复制标题
短暂抗 TCRβ mAb 治疗后糖尿病 NOD 小鼠模型中 PD-1 依赖性自我耐受恢复。
DOI：
10.1007/s00125-015-3564-1
复制
发表时间：
2015
期刊：
影响因子：
8.2
通讯作者：
Stepkowski,StanislawM
中科院分区：
文献类型：
--
作者：
Schroder,PaulM;Khattar,Mithun;Baum,CaitlinE;Miyahara,Yoshihiro;Chen,Wenhao;Vyas,Rohit;Muralidharan,Shravan;Mierzejewska,Beata;Stepkowski,StanislawM
目的/假设T细胞在1型糖尿病的发病机制中起着重要作用，并且人们对开发针对这些细胞的治愈性免疫疗法非常感兴趣。在本研究中，研究了靶向T细胞受体β链（TCRβ）的单克隆抗体（mAb）在小鼠糖尿病模型中预防和逆转疾病的能力。用卵清蛋白特异性T细胞过继转移的（C57 BL/6-Tg（Ins 2-OVA）59 Wehi/WehiJ）小鼠（糖尿病诱导模型）和NOD小鼠（自发性糖尿病模型）用于测试抗TCR β mAb疗法作为预防和逆转1型糖尿病的手段。TCRβ完全预防了RIP-OVAhimice中的疾病，而不诱导炎性细胞因子的释放。瞬时抗TCR β治疗预防了90%的NOD小鼠的糖尿病，并在73%的NOD小鼠发病后逆转了疾病。在1型糖尿病缓解后很长时间，抗TCR β治疗的小鼠能够以正常动力学排斥BALB/c皮肤同种异体移植物，同时维持正常的血肌酐。给药未导致脾脏或胰腺淋巴结中淋巴细胞数量显著减少，但确实导致趋化因子受体9（CCR 9）阳性CD 8 +T细胞百分比降低。值得注意的是，抗TCR β治疗增加了T细胞表面程序性死亡1（PD-1）的表达; PD-1表达对于维持抗TCR β诱导的自身耐受是重要的，因为在阻断PD-1信号传导后，1型糖尿病在小鼠中复发。结论/解释抗TCR β mAb是一种安全有效的免疫疗法，其导致CCR 9 +T细胞数量减少，NOD小鼠T细胞上PD-1表达增加和自身耐受性恢复。
Aims/hypothesisT cells play a major role in the pathogenesis of type 1 diabetes, and there is great interest in developing curative immunotherapies targeting these cells. In this study, a monoclonal antibody (mAb) targeting the T cell receptor β-chain (TCRβ) was investigated for its ability to prevent and reverse disease in mouse models of diabetes.MethodsRIP-OVAhi(C57BL/6-Tg(Ins2-OVA)59Wehi/WehiJ) mice adoptively transferred with ovalbumin-specific T cells (an induced model of diabetes) and NOD mice (a spontaneous model of diabetes) were used to test anti-TCRβ mAb therapy as a means of preventing and reversing type 1 diabetes.ResultsA single dose of anti-TCRβ completely prevented disease in RIP-OVAhimice without inducing the release of inflammatory cytokines. Transient anti-TCRβ therapy prevented diabetes in 90% of NOD mice and reversed the disease after its onset in 73% of NOD mice. Long after the remission of type 1 diabetes, the anti-TCRβ treated mice were able to reject BALB/c skin allografts with normal kinetics while maintaining normoglycaemia. Treatment did not cause significant reductions in lymphocyte numbers in the spleen or pancreatic lymph nodes, but did result in a decreased percentage of chemokine receptor 9 (CCR9) positive, CD8+T cells. Notably, anti-TCRβ therapy increased the expression of programmed death 1 (PD-1) on the surface of the T cells; PD-1 expression is important for maintaining anti-TCRβ-induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling.Conclusions/interpretationAnti-TCRβ mAb is a safe and effective immunotherapy that results in reduced numbers of CCR9+T cells, an increased expression of PD-1 on T cells and the restoration of self-tolerance in NOD mice.