免疫耐受在胰岛移植中的研究进展

胰岛移植已经被公认为治疗胰岛素依赖型糖尿病(IMDD)的有效手段,而现如今胰岛移植的最大障碍是移植排斥反应。目前控制胰岛移植的免疫抑制治疗因其对胰岛细胞的毒性作用及长期应用带来的全身并发症而无法在临床推广,诱导移植术后受体的免疫耐受是防止排斥反应的最理想方法。本文综述了诱导免疫耐受的途径及胰岛移植的最新实验进展。随着研究的深入和免疫学的发展,相信在未来的胰岛移植治疗糖尿病领域,移植排斥现象将能得到高效可靠的解决。     

糖尿病治疗新进展——胰岛细胞移植

随着医学科学的发展和生物学技术的进步,胰岛细胞移植已经被认为是治疗1型糖尿病的一种有效方法。技术上首先要解决好移植物的来源、提取和储存。同时,将移植物导入体内的技术也在不断发展,介入放射学技术发挥了非常重要的作用。研究发现．移植后受体的高血糖明显降低,并能在较长时期保持在正常水平。但胰岛细胞移植后,同样面临移植排斥反应,而在应用免疫抑制剂后又可能引起肝小静脉病等不良反应。利用磁共振和光学成像对标记后的胰岛细胞进行显像,对移植后的胰岛细胞在活体内进行追踪．了解其分布和存活,对于长期监测其功能、改进移植技术和免疫调节方法也很重要。目前面临的问题终将逐一得到解决．胰岛细胞移植很有希望成为治愈糖尿病的方法。     

成人胰岛细胞移植25例次临床研究

目的 建立新型成人胰岛细胞分离纯化方法,观察成人胰岛细胞移植的安全性与有效性.方法 对14例1型糖尿病(T1DM)患者进行PFC与UW液双层冷藏胰腺,Liberase酶消化,COBE 2991型专用胰岛细胞分离机分离及连续密度梯度纯化,获取高纯度与高活性的胰岛细胞.采用外科方法,将短期培养的胰岛细胞经门静脉移植到肝脏内...     

基因工程在克服移植免疫排斥反应及诱导免疫耐受中的应用

有效地控制慢性移植排斥反应和诱导移植免疫耐受是当今移植免疫学研究的热点。基因工程由于在克服移植免疫排斥反应和诱导免疫耐受中具有独特优势而倍受人们关注。然而,在临床应用基因治疗克服移植器官排斥之前,必须确定有效、安全的载体及适宜的靶基因。对该领域的新进展进行了简要综述。     

保护胰岛β细胞的体外研究进展

糖尿病是一种由胰岛素分泌缺陷和（或）胰岛素作用缺陷引起的高血糖症性代谢疾病。自Edmonton临床试验取得成功后,胰岛移植成为一种新型治愈糖尿病的方法。但胰岛β细胞在体外分离过程中极易发生凋亡或死亡,且长期的体外培养或冷冻储存也容易令其胰岛素分泌功能逐渐丧失。因此,有效维持或改善β细胞的成活率及功能对胰岛移植的成功至关重要。对胰岛β细胞的体外保护方法进行阐述,并对其研究前景进行展望。     

同种冷冻乳鼠胰腺胰岛移植对大鼠实验性糖尿病的影响

本实验研究了同种乳胰胰岛移植对链脲佐菌素(STZ)所致大鼠药物性糖尿病的影响。经16周观察发现,新鲜乳胰、组织培养的乳胰和冷冻保存的乳胰,移植于糖尿病大鼠肾被膜下第3天后,宿主血糖下降、血清胰岛素上升、肾被膜下移植组织中免疫金银染色(IGSS)切片可见黑色胰岛素反应阳性细胞,细胞内免疫金银(IGS)含量明显高于糖尿病对照组胰岛中阳性细胞中的含量,逆转糖尿病的有效率为30％～50％。经过组织培养后再冷冻保存的乳胰移植组宿主的体重和血清胰岛素含量上升,血糖浓度下降,其数值均明显地优于其它3个移植组(p<0.01),移植组织中黑色胰岛素反应阳性细胞较多,细胞内IGS含量和逆转糖尿病的有效率(100％)均明显高于其它3个移植组(p<0.01)。     

胰腺或胰岛移植后1型糖尿病复发的预测

胰腺或胰岛移植后的1型糖尿病复发(T1DR)是影响远期移植物功能的关键因素之一。由T1DR导致的移植物功能丧失约占7﹪,与慢性同种排斥反应的发生率相当。然而,由于T1DR引起的复发性高血糖缺乏特异性,导致一直以来临床上T1DR发生被严重低估。移植物组织活检提示特异性靶向β细胞的炎性T细胞浸润是诊断T1DR的“金标准”。但是,作为一种有创性操作,组织活检不作为常规筛查T1DR方法。研究显示监测移植受者的胰岛自身抗体和抗原特异性T细胞对T1DR具有预测价值。本文就胰岛自身抗体和抗原特异性T细胞对预测T1DR作一综述。     

胰岛类器官研究进展

糖尿病被列为对人类健康威胁最大的三类疾病之一,是全球重点关注的公共卫生问题.目前的药物治疗无法从根源上恢复血糖的自主调节.异体胰岛移植能够有效控制糖尿病患者的血糖,但由于尸体胰岛的来源有限,如何在体外获得大量胰岛素分泌细胞是糖尿病移植治疗的关键.近年来,类器官(organoid)培养技术日益发展,给再生医学研究和疾病治疗带来了新思路.胰岛类器官不仅为探究胰岛发育、糖尿病发病机制和治疗策略提供了体外模型,也为糖尿病的细胞治疗提供了新的细胞来源.本文综述了胚胎干细胞、诱导性多能干细胞、转分化细胞和成体干细胞等不同来源的胰岛类器官的研究进展,并探讨如何优化胰岛类器官的培养条件以助力糖尿病的研究与治疗.     

抑制胰岛肝脏移植排异反应有新法

作为重度糖尿病的有效疗法,胰岛肝脏移植目前广受关注,但移植后的排异反应严重影响手术的成功率。日本研究人员新开发出一种抑制排异反应的方法,有望促进胰岛肝脏移植的成功。为调节体内血糖浓度,重度糖尿病患者必须每天接受胰岛素注射。胰岛肝脏移植即从捐献者的胰腺内提取负责分泌胰岛素的细胞组织——胰岛,再把它植入重度糖尿病患者的肝脏。接受胰岛肝脏移植手术的     

植物耐盐性研究进展

土壤盐渍化是影响农业生产和生态环境的严重问题,耕地的减少和淡水资源的不足将迫使人类开发和利用大面积的盐碱地、海岸带和滩涂地带,植物耐盐的机理和耐盐植物的培育研究将成为研究的热点。本文就植物的耐盐性、植物中各种渗透调节剂及植物耐盐相关基因等方面近十年的研究进展作一概要的评价 。     

The role of Islet Neogenesis-Associated Protein (INGAP) in islet neogenesis

Islet Neogenesis-Associated Protein (INGAP) is a member of the Reg family of proteins implicated in various settings of endogenous pancreatic regeneration. The expression of INGAP and other RegIII proteins has also been linked temporally and spatially with the induction of islet neogenesis in animal models of disease and regeneration. Furthermore, administration of a peptide fragment of INGAP (INGAP peptide) has been demonstrated to reverse chemically induced diabetes as well as improve glycemic control and survival in an animal model of type 1 diabetes. Cultured human pancreatic tissue has also been shown to be responsive to INGAP peptide, producing islet-like structures with function, architecture and gene expression matching that of freshly isolated islets. Likewise, studies in normoglycemic animals show evidence of islet neogenesis. Finally, recent clinical studies suggest an effect of INGAP peptide to improve insulin production in type 1 diabetes and glycemic control in type 2 diabetes. Mark Lipsett and Stephen Hanley contributed equally.     

植物耐盐相关基因：SOS基因家族研究进展

土壤盐渍化是影响农业生产和生态环境的一个非常重要的非生物胁迫因素,也是现代生物科学迫切需要解决的问题。利用拟南芥研究植物耐盐相关基因成为该领域的研究热点。几年来,该领域研究成果斐然。本文就SOS基因家族的三个耐盐基因SOS1、SOS2和SOS3的克隆、功能及相互关系作一概要的评述。 Abstract:The soil salination is a significant abiotic stress for agricultural production and ecological environment. The research on salt tolerance represents an important part for basic plant biology. Genetic analysis of salt tolerance genes in Arabidopsis has become a central issue in this research areas. In recent years, efforts from some laboratories in the world have led to some significant progresses in this field. In this paper, we will review the progress in salt tolerance genes SOS(salt overly sensitive):SOS1,SOS2 and SOS3.     

精原干细胞移植及受体制备技术研究进展

精原干细胞移植为研究精子发生、雄性生殖能力及新型转基因技术奠定了基础.尽管已利用小鼠建立了较成熟的移植技术体系,白消安受体制备法和曲细精管及睾丸网移植法已得到广泛应用,但白消安可导致动物较高的死亡率,局部射线照射和无内源性精子发生受体动物的制备费用较昂贵,热处理受体制备法应用范围较窄且效果不稳定;三种移植方法均对操作有较高的技术要求,曲细精管、睾丸输出管移植需要显微注射装置,而睾丸网移植需要超声仪的辅助.而且,移植效果在不同实验间、物种间差异较大,移植效率有待提高,对移植排斥反应的认识也有待进一步深入.对睾丸结构和精原干细胞生物学特性的深入研究,将有助于建立更简单高效的受体制备和移植的方法.     

Neprilysin Impedes Islet Amyloid Formation by Inhibition of Fibril Formation Rather Than Peptide Degradation

Deposition of islet amyloid polypeptide (IAPP) as islet amyloid in type 2 diabetes contributes to loss of β-cell function and mass, yet the mechanism for its occurrence is unclear. Neprilysin is a metallopeptidase known to degrade amyloid in Alzheimer disease. We previously demonstrated neprilysin to be present in pancreatic islets and now sought to determine whether it plays a role in degrading islet amyloid. We used an in vitro model where cultured human IAPP (hIAPP) transgenic mouse islets develop amyloid and thereby have increased β-cell apoptosis. Islet neprilysin activity was inhibited or up-regulated using a specific inhibitor or adenovirus encoding neprilysin, respectively. Following neprilysin inhibition, islet amyloid deposition and β-cell apoptosis increased by 54 and 75%, respectively, whereas when neprilysin was up-regulated islet amyloid deposition and β-cell apoptosis both decreased by 79%. To determine if neprilysin modulated amyloid deposition by cleaving hIAPP, analysis of hIAPP incubated with neprilysin was performed by mass spectrometry, which failed to demonstrate neprilysin-induced cleavage. Rather, neprilysin may act by reducing hIAPP fibrillogenesis, which we showed to be the case by fluorescence-based thioflavin T binding studies and electron microscopy. In summary, neprilysin decreases islet amyloid deposition by inhibiting hIAPP fibril formation, rather than degrading hIAPP. These findings suggest that targeting the role of neprilysin in IAPP fibril assembly, in addition to IAPP cleavage by other peptidases, may provide a novel approach to reduce and/or prevent islet amyloid deposition in type 2 diabetes.     

From Langerhans Islets to Pancreas Transplantation over the past 30 years: A Review with Personal Contributions

Organ, tissue and cell banking is currently an important method used to prevent death of cells in replacement transplantation therapy. From 1975 to 1985 the author performed experimental transplantations of islets isolated by collagenase digestion through injection into the liver through the portal vein, or by transplantation of minced neonatal pancreases under the renal capsule of alloxan or spreptozotocin into severely chronic diabetic rats and mice. Seventy of the 256 transplanted rats and mice were cured for 1 year, i.e. one-third of their life span, at the 3rd to 15th inbreeding and only 2 weeks of immunosuppression by azathioprine or cyclosporin A. The author compares his results with those achieved later with diabetic patients by whole pancreas transplantation, including prevention of diabetic renal and ocular complications, infertility, health of progeny of cured rats, and slow rejection and possibility of cure by repeated transplantation. He welcomes the return to islet transplantation, and possibly also of immunologically tolerant pancreatic stem cell transplantation, or transplantation of subcutaneous fibroblasts, transfected with a complex insulin gene, which will produce adequate insulin to prevent hyperglycemia, as does hepatic pyruvate kinase from an insulin analog, a therapy that will not need permanent immunosuppression.     

肠段移植的研究进展

肠段移植作为外科手术一种替代治疗方式,目前已经广泛应用于临床多个学科,涉及消化系统、泌尿系统和生殖系统,主要包括食管、胃、胆道、膀胱、输尿管、阴道等的重建。现就肠段移植替代不同器官的功能重建做简要的综述。     

Islet hyperplasia in callitrichids

Five callitrichids (three common marmosets -Callithrix jacchus -, a black tufted-eared marmoset-C. penicillata-, and a saddle-back tamarin -Saguinus fuscicollis) were diagnosed with islet hyperplasia by histopathology and immunohistochemistry. All were privately-owned, unrelated callitrichids ranging from 2- to 4-year-old. Relevant findings were anorexia (3/5), vomiting (2/5), ptyalism (1/5), polyuria/polydipsia (1/5), respiratory distress (1/5), hyperglycemia (2/3) and glycosuria (1/1); hyperglycemia and glycosuria were associated with pregnancy in a common marmoset and resolved after reducing simple carbohydrates in diet. All five animals died, three of them after few premonitory signs; in two cases, other concurrent diseases unrelated to islet hyperplasia were considered the cause of death. Additional animals from two facilities had high weight (4), physical obesity (3), polyuria/polydipsia/polyphagia/uriposia (1), hyperglycemia (1), and/or glycosuria (2). Pathologic findings in the deceased callitrichids were: islet hyperplasia (5/5); hemosiderosis (5/5); lipomatosis (4/5) of several tissues (atria, 3/5; pancreas, gall bladder, intestine, esophagus, and thyroid, 2/5; liver, 1/5); pancreatic necrosis or steatonecrosis, and/or acute pancreatitis (3/5); and vacuolation of hepatocytes and renal tubular cells most likely consistent with hepatorenal lipidosis (2/5). The islets of Langerhans were more numerous and larger than in a control, and morphologically normal in all cases, except in a common marmoset that had a few cells with a foamy cytoplasm and shrunken hyperchromatic or picknotic nucleus. Insulin (5/5), glucagon (3/5), and somatostatin (3/5) immunohistochemistry revealed that most cells stained positively for insulin diffusely in their cytoplasm (5/5) (staining restricted to the vascular pole of β-cells in the control). These findings suggest that obesity, insulin resistance and/or type II diabetes may be implicated and thus a prospective study on these diseases in callitrichids is necessary to determine their etiopathogenesis.     

Anti-CD154 mAb and Rapamycin Induce T Regulatory Cell Mediated Tolerance in Rat-to-Mouse Islet Transplantation

Background

Anti-CD154 (MR1) monoclonal antibody (mAb) and rapamycin (RAPA) treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Treg) in the induction and maintenance of the ensuing tolerance.

Methodology/Principal Findings

C57BL/6 mice were treated with MR1/RAPA and received additional monoclonal anti-IL2 mAb or anti CD25 mAb either early (0–28 d) or late (100–128 d) post-transplantation. Treg were characterised in the blood, spleen, draining lymph nodes and within the graft of tolerant and rejecting mice by flow cytometry and immunohistochemistry. Fourteen days of RAPA/MR1 combination therapy allowed indefinite islet graft survival in >80% of the mice. Additional administration of anti-IL-2 mAb or depleting anti-CD25 mAb at the time of transplantation resulted in rejection (100% and 89% respectively), whereas administration at 100 days post transplantation lead to lower rejection rates (25% and 40% respectively). Tolerant mice showed an increase of Treg within the graft and in draining lymph nodes early post transplantation, whereas 100 days post transplantation no significant increase of Treg was observed. Rejecting mice showed a transient increase of Treg in the xenograft and secondary lymphoid organs, which disappeared within 7 days after rejection.

Conclusions/Significances

These results suggest a critical role for Treg in the induction phase of tolerance early after islet xenotransplantation. These encouraging data support the need of developing further Treg therapy for overcoming the species barrier in xenotransplantation.