Cellular Therapy for Type 1 Diabetes using Mesenchymal Stem Cells

： 要治愈1型糖尿病(T1D)，必须克服两个主要障碍：(I)自身免疫反应和(Ii)破坏胰岛素分泌的胰岛/β细胞。免疫疗法，包括使用体外扩增的调节性T细胞(Tregs)或低剂量的白细胞介素2(IL-2)来改善免疫调节，可能能够抑制自身免疫。然而，免疫调节并不能直接刺激β细胞的再生。另一方面，间充质基质/干细胞(MSCs)同时具有免疫调节和再生的特性，是治疗自身免疫性疾病的一种有前途的新干预手段。MSCs是整形外科应用中公认的伤口愈合疗法，目前正在治疗自身免疫性和炎症性疾病、缺血再灌注损伤、糖尿病和其他疾病的临床试验中进行测试。我们的团队和其他人发现，在自发性非肥胖糖尿病(NOD)小鼠体内输注MSCs后，MSCs迁移到受损的胰腺，降低了高血糖，并减弱了伴随Tregs扩张/增殖的Th1免疫反应。最重要的是，骨髓间充质干细胞输注导致NOD小鼠胰腺Treg细胞IL-2和转化生长因子-β受体基因表达增加。瑞典的一项试点临床试验表明，单次输注自体骨髓来源的MSCs可以保护新发的T1D成年患者的胰岛素分泌。这项研究尚未在美国的患者中进行系统的测试，也没有报道解释观察到的益处的机械性研究。脐带间充质干细胞(UC-MSCs)具有细胞产量高、创伤小、发病率低、免疫抑制和再生能力强等优点，是细胞治疗的常用来源。基于上述原则和我们为期一年的R01基金的成功患者登记，我们建议更新一项随机、双盲、安慰剂对照、单中心临床试验，以确定UC-MSC治疗新发T1D患者的疗效。我们的工作假设是，全身应用新鲜体外扩增的MSCs可以通过恢复免疫系统的正常功能和保存/改善T1D患者的胰腺β细胞来减少糖尿病的进展和保护胰岛素的分泌。我们将通过以下目的来检验这一假说：(I)。确定MSC疗法在新发T1D患者中的安全性和有效性，以及(Ii)明确MSC疗法对T1D患者的保护机制并阐明MSC疗法疗效的生物标志物(S)。MSC治疗的早期安全性在我们的第一批7名年龄在18-30岁的成年患者中有记录，这些患者在7个月内接受了多项MSC试验，以治疗各种疾病。骨髓间充质干细胞可能是治疗T1D的重要进展。

: Two major hurdles must be overcome to cure type 1 diabetes (T1D): (i) the autoimmune response and (ii) destruction of insulin-secreting islets/β cells. Immunotherapies, including improved immune regulation using ex vivo expanded regulatory T-cell (Tregs) or low-dose interleukin-2 (IL-2), may be able to suppress autoimmunity. However, immunomodulation is not expected to directly stimulate regeneration of β cells. On the other hand, mesenchymal stromal/stem cells (MSCs) possess both immunomodulatory and regenerative properties and represent a promising new intervention for autoimmune diseases. MSCs are an accepted therapeutic for wound healing in plastic surgery applications and are being tested in clinical trials for the treatment of autoimmune and inflammatory diseases, ischemia reperfusion injuries, diabetes and other diseases. Our group and others found that after infusion into spontaneous non-obese diabetic (NOD) mice, MSCs migrated into the injured pancreas, reduced hyperglycemia and attenuated Th1 immune responses concomitant with the expansion/proliferation of Tregs. Most importantly, MSC infusion led to increased mRNA expression of IL-2 and TGF-β receptors in pancreatic Treg cells in NOD mice. A pilot clinical trial in Sweden showed that a single infusion of autologous bone marrow-derived MSCs preserved insulin secretion in adult patients with new-onset T1D. This study has yet to be systemically tested in patients in the United States and no mechanistic studies have been reported that explain the benefit observed. MSCs derived from umbilical cord (UC-MSCs) show greater cell yield, a less invasive harvesting procedure with associated reduced morbidity, and stronger immunosuppressive and regenerative potential and are a popular source for cell therapy. Based on the above principles and the successful patient enrollment in our one-year R01 grant, we propose a renewal of a randomized, double-blind, placebo- controlled, single-center clinical trial to determine the efficacy of UC-MSC therapy in patients with new-onset T1D. Our working hypothesis is that systemic administration of MSCs freshly expanded ex vivo reduces progression of diabetes and preserves insulin secretion through restoring normal function of the immune system and preservation/improvement of pancreatic β cells in patients with T1D. We will test this hypothesis by the following aims: (i). Determine the safety and efficacy of MSC therapy in patients with new-onset T1D when added to standard-of-care, and (ii) Define the mechanisms of protection and elucidate biomarker(s) of efficacy of MSC therapy in T1D patients. The early safety of MSC therapy is documented in our first 7 adult patients age 18-30 enrolled over 7 months and from multiple MSC Trials for various diseases. MSCs may constitute an important therapeutic advancement for T1D.