BioArtMED 2024-06-15 14:30 四川
Type 1 diabetes mellitus (T1DM), also known as insulin-dependent diabetes mellitus and also known as autoimmune diabetes, is an insulin-deficient disease caused by the loss of β-cells. Pancreatic autoreactive T cells attack β-cells through T cell antigen receptor (TCR)-mediated cytotoxicity and play a leading role in the development and progression of type 1 diabetes. At present, the treatment of T1D is very limited, and the scarcity of donors in pancreatic islet and β-cell transplantation methods has limited its wide application in the clinical treatment of type 1 diabetes. At the same time, treatment methods such as small molecule immunosuppressant drugs (Cyclosporine A) and CD3 monoclonal antibody drugs (Teplizimab and Otelixizumab) that eliminate T cells have disadvantages such as high toxicity and side effects. T cell checkpoints are receptors that exist on the surface of T cells and bind to ligands to send signals to regulate T cell activity, such as PD-1 (programmed cell death protein 1), TIM-3 (T cell immunoglobulin mucin 3) and CTLA-4 (cytotoxic T-lymphocyte-associated). protein 4) and so on. Among them, PD-1 is the most important negative regulatory receptor on the surface of activated T cells. The expression of PD-L1 in normal histiocytes inhibits T cell activity, thereby limiting autoimmune attack and achieving the body's own peripheral immune tolerance. PD-L1 plays a key role in regulating inflammation, and experiments have shown that PD-L1 deficient mice accelerate the progression of diabetes. At the same time, cancer patients who block PD-1/PD-L1 pathway therapy have the occurrence of autoimmune diabetes similar to type 1 diabetes. Galectin-9 (Gal-9) is an inhibitory ligand for Tim-3, and Gal-9 can also interact with PD-1, which induces apoptosis in PD-1+Tim-3+ T cells. In addition, overexpression of Gal-9 has been shown to induce macrophage cell line polarization to M2-type macrophages. M2 macrophages play a crucial role in inhibiting and preventing T1D.
近日，中山大学医学院张旭东副教授团队在美国糖尿病学会官方期刊Diabetes发表了题为Bioengineered cell artificial extracellular vesicles presenting PD-L1 and Gal-9 ameliorate new-onset type 1 diabetes的研究论文。 研究团队对小鼠巨噬细胞系进行基因工程编辑，使其过表达PD-L1和Galectin-9，工程细胞呈现M2型巨噬细胞特征。 利用工程细胞系制备高表达PD-L1和Galectin-9的人工细胞外囊泡，该囊泡可到达发炎的胰腺组织，抑制胰岛自身反应性T细胞的活性，从而保护分泌胰岛素的β-细胞免受攻击，为1型糖尿病的缓解和治疗提供了新的思路。
Figure 1. PD-L1/Gal-9 cell membrane vesicles are used for immune intervention to improve the morbidity of type 1 diabetic mice
We overexpressed PD-L1 and Gal-9 in Raw264.7 cells, followed by the preparation of artificial cell membrane vesicles presenting PD-L1 and Gal-9. b. PD-L1-Gal-9 aEVs attached to PD-1 and Tim-3 on autoreactive T cells, respectively. Subsequently, these aEVs inactivate autoreactive T cells and induce apoptosis, thereby protecting β-cells from damage.
Associate Professor Xudong Zhang's team genetically engineered a mouse macrophage cell line to overexpress two key immunosuppressive molecules, PD-L1 and Gal-9. Overexpression of Gal-9 polarizes Raw264.7 macrophages into M2-type macrophages with immunosuppressive properties. Subsequently, artificial extracellular vesicles (aEVs) expressing PD-L1 and Gal-9 were prepared using engineered cell membranes. PD-L1/Gal-9 aEVs can inhibit islet-specific T cell activity and induce apoptosis through PD-1/PD-L1 or TIM-3/Gal-9 interactions. In addition, PD-L1-Gal-9 aEVs significantly promote effector T cell apoptosis in vitro and promote the differentiation and formation of spleen-derived regulatory T cells (Tregs). PD-L1-Gal-9 aEVs showed good therapeutic effect in a mouse model of NOD diabetes, effectively alleviating hyperglycemia and slowing down the progression of T1D in new-onset NOD mice. Further analysis showed that PD-L1-Gal-9 aEVs significantly reduced the proportion and activity of pancreatic infiltrating CD4+ and CD8+ T cells. This study provides a new way of thinking about the treatment of type 1 diabetes.
The first unit of the research paper is: Shenzhen Key Laboratory of Systemic Medicine for Inflammatory Diseases, School of Medicine, Sun Yat-sen University. Sun Yat-sen University School of Medicine graduate students Zhaoxin Yang, Zhirang Zhang and Liyan Li are the co-first authors of this research paper. Associate Professor Zhang Xudong from Sun Yat-sen University School of Medicine, Associate Professor Zheng Yi from the Center for Experimental Medicine (CEM) at Shenzhen Hospital of the University of Chinese Academy of Sciences, and Professor Wu Benqing from the Department of Pediatrics are the co-corresponding authors of the paper.
Original link: https://doi.org/10.2337/db23-0987