Schroder Paul M, Khattar Mithun, Baum Caitlin E, Miyahara Yoshihiro, Chen Wenhao, Vyas Rohit, Muralidharan Shravan, Mierzejewska Beata, Stepkowski Stanislaw M
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, 3000 Arlington Avenue, HEB 263A, Toledo, OH, 43614, USA.
Diabetologia. 2015 Jun;58(6):1309-18. doi: 10.1007/s00125-015-3564-1. Epub 2015 Mar 21.
AIMS/HYPOTHESIS: T 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.
RIP-OVA(hi) (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.
A single dose of anti-TCRβ completely prevented disease in RIP-OVA(hi) mice 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/INTERPRETATION: Anti-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.
目的/假设：T细胞在1型糖尿病发病机制中起主要作用，开发针对这些细胞的治愈性免疫疗法备受关注。在本研究中，研究了一种靶向T细胞受体β链（TCRβ）的单克隆抗体（mAb）在糖尿病小鼠模型中预防和逆转疾病的能力。
将卵清蛋白特异性T细胞过继转移的RIP-OVA(hi)（C57BL/6-Tg(Ins2-OVA)59Wehi/WehiJ）小鼠（糖尿病诱导模型）和NOD小鼠（糖尿病自发模型）用于测试抗TCRβ mAb疗法作为预防和逆转1型糖尿病的手段。
单剂量抗TCRβ可完全预防RIP-OVA(hi)小鼠发病，且不诱导炎性细胞因子释放。短暂抗TCRβ治疗可预防90%的NOD小鼠患糖尿病，并使73%的NOD小鼠在发病后疾病逆转。在1型糖尿病缓解很久之后，接受抗TCRβ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，同时维持血糖正常。治疗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（CCR9）阳性的CD8(+) T细胞百分比降低。值得注意的是，抗TCRβ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TCRβ诱导的自身耐受性很重要，因为在阻断PD-1信号后小鼠会复发1型糖尿病。
结论/解读：抗TCRβ mAb是一种安全有效的免疫疗法，可减少CCR9(+) T细胞数量，增加T细胞上PD-1的表达，并恢复NOD小鼠的自身耐受性。
