Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Protect from Transfer of Autoimmune Diabetes by Shifting the Balance between Effector T Cells and Regulatory T Cells
Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Protect from Transfer of Autoimmune Diabetes by Shifting the Balance between Effector T Cells and Regulatory T Cells
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DOI：
10.4049/jimmunol.1900127
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发表时间：
2019-07-01
影响因子：
4.4
通讯作者：
Haskins, Kathryn
中科院分区：
文献类型：
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作者：
Jamison, Braxton L.;Neef, Tobias;Haskins, Kathryn
CD4 T细胞在促进1型糖尿病自身免疫发展中起关键作用。糖尿病源性CD4 T细胞克隆BDC-2.5最初从NOD小鼠中分离出来，已被广泛用于研究自身反应性CD4 T细胞和相关Ags在自身免疫性糖尿病中的作用。我们实验室最近的研究表明，BDC-2.5 T细胞的Ag是一种混合胰岛素肽（2.5HIP），由胰岛素c肽片段与铬粒蛋白a （ChgA）的肽融合而成，内源性2.5HIP反应性T细胞是NOD小鼠自身免疫病理的主要因素。本研究的目的是确定负载2.5HIP Ag （2.5HIP偶联PLG NPs）的聚乳酸-羟基乙酸酯（PLG）纳米颗粒（NPs）是否能耐受BDC-2.5 T细胞。在过继性转移模型中，我们发现输注2.5 hip -偶联PLG NPs可以通过诱导能量损害BDC-2.5 T细胞产生促炎细胞因子的能力，从而导致Foxp3（+）调节性T细胞与ifn - γ(+)效应T细胞的比例增加，从而预防糖尿病。据我们所知，这项工作是第一次使用混合胰岛素肽或任何新表位来重新教育糖尿病源性T细胞，并可能对开发针对1型糖尿病患者的ag特异性治疗具有重要意义。
CD4 T cells play a critical role in promoting the development of autoimmunity in type 1 diabetes. The diabetogenic CD4 T cell clone BDC-2.5, originally isolated from a NOD mouse, has been widely used to study the contribution of autoreactive CD4 T cells and relevant Ags to autoimmune diabetes. Recent work from our laboratory has shown that the Ag for BDC-2.5 T cells is a hybrid insulin peptide (2.5HIP) consisting of an insulin C-peptide fragment fused to a peptide from chromogranin A (ChgA) and that endogenous 2.5HIP-reactive T cells are major contributors to autoimmune pathology in NOD mice. The objective of this study was to determine if poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) loaded with the 2.5HIP Ag (2.5HIP-coupled PLG NPs) can tolerize BDC-2.5 T cells. Infusion of 2.5HIP-coupled PLG NPs was found to prevent diabetes in an adoptive transfer model by impairing the ability of BDC-2.5 T cells to produce proinflammatory cytokines through induction of anergy, leading to an increase in the ratio of Foxp3(+) regulatory T cells to IFN-gamma(+) effector T cells. To our knowledge, this work is the first to use a hybrid insulin peptide, or any neoepitope, to re-educate diabetogenic T cells and may have significant implications for the development of an Ag-specific therapy for type 1 diabetes patients.