Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
Acta Biomater. 2023 Aug;166:95-108. doi: 10.1016/j.actbio.2023.05.008. Epub 2023 May 5.
Islet transplantation is regarded as the most promising therapy for type 1 diabetes. However, both hypoxia and immune attack impair the grafted islets after transplantation, eventually failing the islet graft. Although many studies showed that biomaterials with nanoscale pores, like hydrogels, could protect islets from immune cells, the pores on biomaterials inhibited vascular endothelial cells (VECs) to creep in, which resulted in poor revascularization. Thus, a hydrogel device that can facilitate in situ immune modulations without the cost of poor revascularization should be put forward. Accordingly, we designed a spA-modified hydrogel capturing anti-HMGB1 mAB (mAB-spA Gel): the Staphylococcus aureus protein A (spA) was conjugated on the network of hydrogel to capture anti-HMGB1mAB which can inactivate immune cells, while the pore sizes of the hydrogel were more than 100μm which allows vascular endothelial cells (VECs) to creep in. In this study, we screened the optimal spA concentration in mAB-spA Gel according to the physical properties and antibody binding capability, then demonstrated that it could facilitate in situ immunomodulation without decreasing the vessel reconstruction in vitro. Further, we transplanted islet graft in vivo and showed that the survival of islets was elongated. In conclusion, mAB-spA Gel provided an alternative islet encapsulation strategy for type 1 diabetes. STATEMENT OF SIGNIFICANCE: Although various studies have shown that the backbone of the hydrogels can isolate islets grafts from immune cells and the survival of the islets can be prolonged by this way, it is also reported that when the pore size of the backbone is too small the revascularization will be adversely affected. According to this point, it is hard to adjust hydrogel's pore size to protect the islets from the immune attack while allowing endothelial vascular cells to creep in. To solve this dilemma, we designed an immunomodulatory hydrogel inhibiting the activation of T cells by immunosuppressive IgGs instead of the backbone network, so the hydrogel can prolong the survival of islets without the sacrifice of revascularization.
胰岛移植被认为是治疗 1 型糖尿病最有前途的方法。然而，缺氧和免疫攻击都会损害移植后的胰岛，最终导致胰岛移植物失功。尽管许多研究表明，具有纳米级孔径的生物材料（如水凝胶）可以保护胰岛免受免疫细胞的攻击，但生物材料上的孔径会抑制血管内皮细胞（VEC）的爬行，从而导致血管再生成不良。因此，应该提出一种能够促进原位免疫调节而不会降低血管再生成的水凝胶装置。因此，我们设计了一种 spA 修饰的水凝胶捕获抗 HMGB1 mAB（mAB-spA 凝胶）：金黄色葡萄球菌蛋白 A（spA）被连接到水凝胶的网络上，以捕获可以使免疫细胞失活的抗 HMGB1 mAB，而水凝胶的孔径大于 100μm，允许血管内皮细胞（VEC）爬行。在这项研究中，我们根据物理性质和抗体结合能力筛选了 mAB-spA 凝胶中的最佳 spA 浓度，然后证明它可以促进原位免疫调节，而不会降低体外血管重建。此外，我们在体内移植胰岛移植物，结果表明胰岛的存活时间延长。总之，mAB-spA 凝胶为 1 型糖尿病提供了一种替代的胰岛包封策略。
尽管各种研究表明水凝胶的骨架可以将胰岛移植物与免疫细胞隔离，并通过这种方式延长胰岛的存活时间，但也有报道称，当骨架的孔径太小时，血管再生成会受到不利影响。根据这一点，很难调整水凝胶的孔径以保护胰岛免受免疫攻击，同时允许内皮血管细胞爬行。为了解决这个困境，我们设计了一种免疫调节水凝胶，通过抑制免疫球蛋白 IgG 来抑制 T 细胞的激活，而不是通过骨架网络，因此水凝胶可以延长胰岛的存活时间，而不会牺牲血管再生成。
