背景:移植的人胰岛组织的稀缺和需要免疫抑制药物来预防同种异体移植物的排斥反应,阻碍了通过胰岛移植治疗自身免疫性1型糖尿病(T1DM)。然而,过继转移的骨髓细胞(BMC)治疗有希望,这已经成为未来药物的有利途径。BMC有可能显著影响一系列疾病的替代和再生疗法。包括糖尿病,并且已经证明了抗糖尿病的作用。
目的:本研究的主要目的是评估过继性转移的来自初始小鼠(nBMC)或糖尿病小鼠(dBMC)的骨髓细胞在治疗T1DM小鼠模型中的有效性。
方法:雄性瑞士白化病小鼠饥饿16小时,然后以40mg/kg体重的剂量连续5天注射链脲佐菌素(STZ)以诱导T1DM。14天后,糖尿病小鼠分为四组。第一组作为糖尿病对照,用柠檬酸钠缓冲液治疗,而其他三组治疗两周,分别,胰岛素(皮下剂量为8U/kg/天),nBMC(静脉内剂量为1×106个细胞/小鼠/一次),和dBMC(以1×106个细胞/小鼠/一次的剂量静脉内)。
结果:值得注意的是,对STZ诱导的T1DM小鼠施用过继转移的nBMC或过继转移的dBMC可显著改善血糖状况,伴随着血糖和糖化血红蛋白(HbA1C%)水平的显着降低,最终将对照小鼠的血清胰岛素水平恢复到初始状态。对STZ诱导的T1DM小鼠施用nBMC或dBMC导致血清中炎性细胞因子标志物水平显著降低,包括干扰素-γ(INF-γ),肿瘤坏死因子-α(TNF-α),肿瘤生长因子-β(TGF-β),白细胞介素-1β(L-1β),交织-4(IL-4),白细胞介素-6(IL-6),和白细胞介素-10(IL-10)。此外,STZ诱导的T1DM小鼠,当用nBMC或dBMC治疗时,总免疫球蛋白(Ig)水平显着上升。此外,胰岛细胞自身抗体(ICA)和胰岛素自身抗体(IAA)水平显著降低.此外,STZ诱导的T1DM小鼠血清中锌转运体8抗原蛋白(ZnT8)显著升高,胰岛抗原2蛋白(IA-2),和谷氨酸脱羧酶抗原蛋白(GAD)水平。有趣的是,在用nBMC或dBMC治疗的STZ诱导的T1DM小鼠中,施用nBMC或dBMC导致IA-2蛋白表达增强.此外,丙二醛(MDA)水平升高,而未治疗的STZ诱导的T1DM小鼠的过氧化氢酶(CAT)和超氧化物歧化酶(SOD)水平降低。然而,当向STZ诱导的T1DM小鼠施用nBMC或dBMC时,它对减少氧化应激有显著影响。这是通过降低血清中MDA的水平并增强酶抗氧化剂如CAT和SOD的活性来实现的。STZ诱导的T1DM小鼠肝脏酶ALT和AST水平显着升高,以及肌酐和尿素水平升高。考虑到肝脏和肾脏在代谢和排泄中的关键作用,这项研究进一步检查了对STZ诱导的T1DM小鼠施用nBMC或dBMC的效果。值得注意的是,这些细胞的施用减轻了观察到的效果。
结论:本研究表明,在T1DM治疗中利用过继转移的nBMC或过继转移的dBMC导致血糖水平显著下降,可能归因于它们增强胰岛素分泌和改善胰岛性能的能力。此外,BMCs可能通过免疫调节对糖尿病小鼠的胰岛发挥有益作用,抗氧化剂,抗炎,和抗氧化应激特性。
BACKGROUND: The scarcity of transplanted human islet tissue and the requirement for immunosuppressive drugs to prevent the rejection of allogeneic grafts have hindered the treatment of autoimmune type 1 diabetes mellitus (T1DM) through islet transplantation. However, there is hope in adoptively transferred bone marrow cells (BMCs) therapy, which has emerged as a propitious pathway for forthcoming medications. BMCs have the potential to significantly impact both replacement and regenerative therapies for a range of disorders, including diabetes mellitus, and have demonstrated anti-diabetic effects.
OBJECTIVE: The main goal of this study is to evaluate the effectiveness of adoptively transferred bone marrow cells derived from either naïve mice (nBMCs) or diabetic mice (dBMCs) in treating a T1DM mice model.
METHODS: Male Swiss albino mice were starved for 16 h and then injected with streptozotocin (STZ) at a dose of 40 mg/kg body weight for 5 consecutive days to induce T1DM. After 14 days, the diabetic mice were distributed into four groups. The first group served as a diabetic control treated with sodium citrate buffer, while the other three groups were treated for two weeks, respectively, with insulin (subcutaneously at a dose of 8 U/kg/day), nBMCs (intravenously at a dose of 1 × 106 cells/mouse/once), and dBMCs (intravenously at a dose of 1 × 106 cells/mouse/once).
RESULTS: It is worth noting that administering adoptively transferred nBMCs or adoptively transferred dBMCs to STZ-induced T1DM mice resulted in a significant amelioration in glycemic condition, accompanied by a considerable reduction in the level of blood glucose and glycosylated hemoglobin % (HbA1C %), ultimately restoring serum insulin levels to their initial state in control mice. Administering nBMCs or dBMCs to STZ-induced T1DM mice led to a remarkable decrease in levels of inflammatory cytokine markers in the serum, including interferon-γ (INF-γ), tumor necrosis factor- α (TNF-α), tumor growth factor-β (TGF-β), interleukin-1 β (L-1β), interlekin-4 (IL-4), interleukin-6 (IL-6), and interleukin-10 (IL-10). Additionally, STZ-induced T1DM mice, when treated with nBMCs or dBMCs, experienced a notable rise in total immunoglobulin (Ig) level. Furthermore, there was a significant reduction in the levels of islet cell autoantibodies (ICA) and insulin autoantibodies (IAA). Furthermore, the serum of STZ-induced T1DM mice showed a significant increase in Zinc transporter 8 antigen protein (ZnT8), islet antigen 2 protein (IA-2), and glutamic acid decarboxylase antigen protein (GAD) levels. Interestingly, the administration of nBMCs or dBMCs resulted in a heightened expression of IA-2 protein in STZ-induced T1DM mice treated with nBMCs or dBMCs. Furthermore, the level of malondialdehyde (MDA) was increased, while the levels of catalase (CAT) and superoxide dismutase (SOD) were decreased in non-treated STZ-induced T1DM mice. However, when nBMCs or dBMCs were administered to STZ-induced T1DM mice, it had a significant impact on reducing oxidative stress. This was accomplished by reducing the levels of MDA in the serum and enhancing the activities of enzymatic antioxidants like CAT and SOD. STZ-induced T1DM mice displayed a significant elevation in the levels of liver enzymes ALT and AST, as well as heightened levels of creatinine and urea. Considering the crucial roles of the liver and kidney in metabolism and excretion, this research further examined the effects of administering nBMCs or dBMCs to STZ-induced T1DM mice. Notably, the administration of these cells alleviated the observed effects.
CONCLUSIONS: The present study suggests that utilizing adoptively transferred nBMCs or adoptively transferred dBMCs in the treatment of T1DM led to noteworthy decreases in blood glucose levels, possibly attributed to their capacity to enhance insulin secretion and improve the performance of pancreatic islets. Additionally, BMCs may exert their beneficial effects on the pancreatic islets of diabetic mice through their immunomodulatory, antioxidant, anti-inflammatory, and anti-oxidative stress properties.