1型糖尿病的免疫耐受治疗

1型糖尿病的发病机制是自身免疫性胰岛炎.其胰岛素缺乏是由于胰腺中大量胰岛β细胞被免疫系统攻击所致.通过各种不同的途径建立胰岛β细胞免疫耐受,包括造血干细胞的移植、过继不同功能状态的树突状细胞、口服胰岛素及其相关疫苗的输入、谷氨酸脱羧酶65疫苗、抗CD3、CD20单克隆抗体以及联合免疫干预等免疫耐受治疗,可延缓l型糖尿病...     

免疫干预联合骨髓干细胞移植治疗早发1型糖尿病的前景

1型糖尿病是由于胰岛β细胞进行性自身免疫性破坏所引起的,其治疗需要自身免疫件反应的逆转、胰岛β细胞的再牛和功能恢复.适度的免疫抑制剂治疗早发1型糖尿病可阻止胰岛β细胞进一步损失、减少胰岛素的使用,但不能阻止并发症的恶化.最近许多研究报道,免疫干预联合骨髓干细胞移植可维持较长的胰岛素非依赖时间,然而其能有效治疗早发1型槠尿病的机制尚未清楚.     

胰岛自身免疫与2型糖尿病

胰岛自身免疫不仅是1型糖尿病的发病基础,而且也是2型糖尿病的发病表现.研究表明,伴严重的胰岛素抵抗和β细胞功能损伤的2型糖尿病患者体内可检测到胰岛自身抗体、促炎细胞因子或胰岛反应性T细胞.这些免疫及炎性反应因子是产生胰岛自身免疫反应的关键因素,也是2型糖尿病慢性炎性反应的发病机制.因此,研究胰岛自身免疫与2型糖尿病的关系,将为2型糖尿病的治疗提供新思路.     

自体造血干细胞移植治疗1型糖尿病的前景与出路

1A型糖尿病的“根治性”治疗方向在于免疫紊乱的纠正和受损胰岛β细胞的完全修复.前者借助于免疫干预治疗,后者借助于细胞替代治疗.自体造血干细胞移植(AHSCT)在使用了大剂量免疫抑制剂和自体预先采集的造血干细胞回输后,拟通过造血和免疫系统的重建和干细胞对胰岛β细胞促进再生作用,来达到长期缓解糖尿病的临床治疗目的.其目前适用的人群仅限于1A型初发糖尿病患者,伴有残存的胰岛功能.同时,AHSCT的具体机制尚不明朗,临床疗效个体差异较大,其未来和出路还面临着巨大挑战.     

自体外周造血干细胞移植——治疗1型糖尿病的新曙光

1型糖尿病以自身免疫性胰岛炎和胰岛β细胞损伤为病理特征.尽管胰岛素强化治疗能使1型糖尿病患者实现良好的血糖控制,但该方案难以完全阻止糖尿病并发症的发生.最大限度的保存1型糖尿病患者自身的胰岛功能,是预防或延缓糖尿病并发症的关键.近年研究显示:自体外周造血干细胞移植(AHSCT)可诱导1型糖尿病患者实现免疫耐受,并改善其胰岛功能.本文将重点介绍采用该方案治疗中国人群初发1型糖尿病患者(多以酮症酸中毒起病)的临床研究结果( NCT01341899,ClinicalTrials.gov),并简要阐述AHSCT治疗1型糖尿病的可能机制和应用前景.     

胰岛干细胞的研究进展

胰岛细胞移植是治疗1型糖尿病的可行性方法,但面临组织来源缺乏和免疫排斥等难题。干细胞是具有自我复制能力和多种分化潜能的细胞。研究发现,在胰腺导管细胞和胰岛中存在成体胰岛干细胞,而胚胎干细胞经适当的培养、诱导可以分化为具有胰岛特征并可分泌胰岛素的细胞。这些研究进展为糖尿病的细胞治疗带来了新的希望。     

1型糖尿病的免疫防治

1型糖尿病(T1DM)是遗传与环境因素共同作用所致的自身免疫性疾病.为预防和延缓T1DM高危人群自身免疫性胰岛炎的发生,阻止新发T1DM残存胰岛β细胞进一步遭受免疫破坏,T1DM的免疫防治有了较大进展.根据干预实施时机的不同,分为一级、二级和三级预防.主要通过饮食干预、自身抗原疫苗接种及单克隆抗体治疗等措施诱导自身免疫耐受,改善免疫调节,减少胰岛β细胞凋亡.许多临床研究对T1DM的免疫干预进行了探索,并进行了谷氨酸脱羧酶(GAD)疫苗、抗CD3单克隆抗体、DiaPep277等药物的临床研究,为T1DM的防治提供了新启示.     

1型糖尿病的免疫治疗

1型糖尿病（T1DM）是一种自身免疫性疾病,人们希望基于发病机制进行免疫干预治疗可以达到预防和逆转 T1DM的目的。近30余年,免疫干预临床试验逐渐开展,包括免疫调节药物、调节性T细胞、干细胞治疗和胰岛移植 等。尽管这些试验通过抑制自身免疫应答或胰岛B细胞替代,可以延缓胰岛B细胞功能的衰退或短期内脱离胰岛素 治疗,但仍有各自的局限性。文章将结合最新的临床试验数据对免疫干预治疗T1DM的研究进展进行总结和展望。     

2型糖尿病患者血清谷氨酸脱羧酶抗体和胰岛细胞抗体检测临床意义

谷氨酸脱羧酶抗体(GADA)和胰岛细胞抗体(ICA)的检测对1型糖尿病早期诊断有重要意义.然而,部分临床诊断为2型糖尿病的患者中存在1型糖尿病的免疫指标,提示这些患者存在自身免疫性胰岛炎.本研究旨在了解2型糖尿病患者中GADA和ICA的阳性率,比较抗体阳性与抗体阴性2型糖尿病患者的临床特征.     

糖尿病与胰岛素自身免疫

糖尿病的一个病因是胰岛的自身免疫产生胰岛炎。在人类幼年型糖尿病发病早期死亡,解剖发现胰岛炎的病例不少,这种病人对胰岛有细胞性免疫的报告也很多。用注射胰岛素得到免疫性的豚鼠血清,给另外的动物注射可引起一过性糖尿病,也说明胰岛素     

骨髓移植与1型糖尿病

自体和同种异体骨髓移植治疗难治性自身免疫性疾病是近年来研究的热点。1型糖尿病是最常见的器官特异性自身免疫性疾病之一,自体骨髓移植能够缓解自身免疫性胰岛炎,重建相对正常的免疫系统;而同种异体骨髓移植则不仅能纠正自身免疫状态,而且能对供者的胰岛产生特异性免疫耐受。因此,骨髓移植对1型糖尿病的防治以及胰岛移植等都具有重要的价值。     

Neutrophils in type 1 diabetes

Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin‐producing pancreatic β‐cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β‐cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil‐derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell–cell interactions with other immune and non‐immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes.     

Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes

The c-Jun NH(2)-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of beta cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4(+) T cells from JNK2-deficient nonobese diabetic mice produced less IFN-gamma but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1/Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.     

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody

Inflammatory destruction of insulin-producing beta cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4-7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44-hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.     

Novel therapy for type 1 diabetes: Autologous hematopoietic stem cell transplantation

Type 1 diabetes is characterized pathologically by autoimmune insulitis‐related islet β‐cell destruction. Although intensive insulin therapy for patients with type 1 diabetes can correct hyperglycemia, this therapy does not prevent all diabetes‐related complications. Recent studies have shown that autologous hematopoietic stem cell transplantation (HSCT) is a promising new approach for the treatment of type 1 diabetes by reconstitution of immunotolerance and preservation of islet β‐cell function. Herein we discuss the therapeutic efficacy and potential mechanisms underlying the action of HSCT and other perspectives in the clinical management of type 1 diabetes.     

Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells.

Transplantation of bone marrow cells from nonobese diabetic (NOD) mice, a model for type 1 diabetes mellitus, to C3H/HeN mice, which express I-E alpha molecules and have aspartic acid at residue 57 of the I-A beta chain, induced insulitis followed by overt diabetes in the recipient C3H/HeN mice more than 40 weeks after bone marrow transplantation. When cyclosporin A, which perturbs T-cell functions, was injected intraperitoneally into [NOD----C3H/HeN] chimeric mice daily for 1 month, the chimeric mice developed insulitis and overt diabetes within 20 weeks following bone marrow transplantation. Transplantation of bone marrow cells from (NZW x BXSB)F1 mice, which develop lupus nephritis, myocardial infarction, and idiopathic thrombocytopenic purpura, into C3H/HeN or C57BL/6J mice induced in the recipient strains both lupus nephritis and idiopathic thrombocytopenic purpura more than 3 months after transplantation. Transplantation of a stem-cell-enriched population from (NZW x BXSB)F1 mice into normal mice also induced autoimmune disease in the recipients. These results indicate that both systemic autoimmune disease and organ-specific autoimmune disease originate from defects that reside within the stem cells; the thymus and environmental factors such as sex hormones appear to act only as accelerating factors.     

Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Nonobese diabetic mice spontaneously develop diabetes that is caused by autoimmune cell-mediated destruction of pancreatic beta cells. Here we report that surgical removal of 90% of pancreatic tissue before onset of insulitis induced a long-term diabetes-free condition in nonobese diabetic mice. Pancreatectomy after development of moderate insulitis had no effect on the course of diabetes. The effect of pancreatectomy was abrogated with subsequent development of diabetes by infusion of islet-cell-specific T lymphocytes and by transplantation of pancreatic islets. Lymphocytes from pancreatectomized diabetes-free mice exhibited low response to islet cells but responded normally to alloantigens. These results suggest that the islet cell mass plays a critical role in development of autoimmune diabetes.