Elizondo Diana M, de Oliveira Rekowsky Lais L, de Sa Resende Ayane, Seenarine Jonathan, da Silva Ricardo Luis Louzada, Ali Jamel, Yang Dazhi, de Moura Tatiana, Lipscomb Michael W
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, 21250, USA.
Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
Tissue Eng Regen Med. 2025 Jan;22(1):43-55. doi: 10.1007/s13770-024-00685-7. Epub 2024 Dec 30.
Type 1 diabetes (T1D) results in autoreactive T cells chronically destroying pancreatic islets. This often results in irreplaceable loss of insulin-producing beta cells. To reverse course, a combinatorial strategy of employing glucose-responsive insulin restoration coupled with inhibiting autoreactive immune responses is required.
Non-obese diabetic mice received a single intraperitoneal implantation of a novel biomaterial co-seeded with insulin-producing islets and T regulatory cells (Tregs). Controls included biomaterial seeded solely with islets, or biomaterial only groups. Mice were interrogated for changes in inflammation and diabetes progression via blood glucose monitoring, multiplex serum cytokine profiling, flow cytometry and immunohistochemistry assessments.
Islet and Tregs co-seeded biomaterial recipients had increased longevity, insulin secretion, and normoglycemia through 180 days post-implantation compared to controls. Serum profile revealed reduced TNFα, IFNγ, IL-1β and increased IL-10, insulin, C-Peptide, PP and PPY in recipients receiving co-seeded biomaterial. Evaluation of the resected co-seeded biomaterial revealed reduced infiltrating autoreactive CD8 + and CD4 + T cells concomitant with sustained presence of Foxp3 + Tregs; further analysis revealed that the few infiltrated resident effector CD4 or CD8 T cells were anergic, as measured by low levels of IFNγ and Granzyme-B upon stimulation when compared to controls. Interestingly, studies also revealed increased Tregs in the pancreas. However, there was no restoration of the pancreas beta cell compartment, suggesting normoglycemia and production of insulin levels were largely supported by the implanted co-seeded biomaterial.
These studies show the efficacy of a combinatorial approach seeding Tregs with pancreatic islets in a novel self-assembling organoid for reversing T1D.
1型糖尿病（T1D）导致自身反应性T细胞长期破坏胰岛。这通常会导致产生胰岛素的β细胞不可替代地丧失。为了扭转这种情况，需要采用葡萄糖反应性胰岛素恢复与抑制自身反应性免疫反应相结合的策略。
非肥胖糖尿病小鼠单次腹腔内植入一种新型生物材料，该材料共接种了产生胰岛素的胰岛和调节性T细胞（Tregs）。对照组包括仅接种胰岛的生物材料组或仅生物材料组。通过血糖监测、多重血清细胞因子分析、流式细胞术和免疫组织化学评估，观察小鼠炎症和糖尿病进展的变化。
与对照组相比，共接种胰岛和Tregs的生物材料受体在植入后180天内寿命延长、胰岛素分泌增加且血糖正常。血清分析显示，接受共接种生物材料的受体中肿瘤坏死因子α（TNFα）、干扰素γ（IFNγ）、白细胞介素-1β（IL-1β）减少，白细胞介素-10（IL-10）、胰岛素、C肽、胰多肽（PP）和胰抑素（PPY）增加。对切除的共接种生物材料进行评估发现，浸润的自身反应性CD8 +和CD4 + T细胞减少，同时Foxp3 + Tregs持续存在；进一步分析表明，与对照组相比，少数浸润的驻留效应性CD4或CD8 T细胞在受到刺激时，通过低水平的IFNγ和颗粒酶B测量显示为无反应性。有趣的是，研究还发现胰腺中的Tregs增加。然而，胰腺β细胞区室并未恢复，这表明血糖正常和胰岛素水平的产生在很大程度上由植入的共接种生物材料支持。
这些研究表明，在一种新型自组装类器官中，将Tregs与胰岛共接种的联合方法对于逆转T1D具有疗效。
