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Engineering pancreatic islets with TGβ protein to overcome rejection

用 TGβ 蛋白改造胰岛以克服排斥反应

基本信息

批准号：
9066573
负责人：
Haval Shirwan
金额：
$ 18.75万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-12 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066573
关键词：
Affect Affinity Alloantigen Allogenic Antigens Applications Grants Area Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biological Biotin C57BL/6 Mouse Cells Characteristics Chimeric Proteins Chronic Clinical Data Development Diabetes Mellitus Diabetic mouse Disease Economic Burden Ectopic Expression Engineering Failure Family suidae Fibrosis Generations Goals Graft Rejection Graft Survival Health Homeostasis Human IL2RA gene Immune Immune response Immune system Immunosuppression Immunosuppressive Agents Inbred BALB C Mice Inbred NOD Mice Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Ligands Maintenance Mediating Membrane Memory Methods Modeling Molecular Molecular Chaperones Morbidity - disease rate Mus Natural regeneration Pancreas Pancreas Transplantation Pharmaceutical Preparations Play Population Proteins Protocols documentation Recovery Regulation Regulatory T-Lymphocyte Reporting Rodent Model Role Safety Series Signal Transduction Sirolimus Source Splenocyte Streptavidin Suggestion Surface System T-Lymphocyte Therapeutic To autoantigen Toxic effect Transforming Growth Factor beta Transgenic Organisms Transplantation Viral Vector base clinically relevant crosslink design diabetic effective therapy efficacy testing gene therapy human disease immune function immunoregulation improved functioning islet lymph nodes macrophage mortality mouse model novel novel strategies pleiotropism prevent receptor standard care

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) continues to be a major source of morbidity and mortality in over 0.9% US population with an economic burden in billions of dollars. The two current methods used to treat T1D are insulin therapy and allogeneic islet/pancreas transplantation (Tx), both of which have major limitations. Insulin administration does not completely prevent the complications associated with diabetes. Allogeneic islet/pancreas Tx suffers from rejection as well as renal and islet toxicities associated with chronic use of immunosuppressive drugs. Therefore, the primary objective of this grant proposal is to establish a novel immunomodulatory protocol to confer tolerance to allogeneic islet grafts in the absence of continuous immunosuppression. This will be achieved by engineering allogeneic islets ex vivo to transiently display on their surface a novel form of TGFß1, SA-TGFß, protein and use the engineered islets to induce tolerance and treat T1D using rodent models. T1D and allogeneic islet cell destruction is primarily mediated by T cells directed at unique beta cell and Tx antigens. Controlling the function of T pathogenic cells is, therefore, critical to tolerance induction to auto/alloantigens and treatment of T1D using allogeneic islets. We herein propose to use SA-TGFß as an immunomodulatory molecule to achieve this goal. TGFß1 has pleiotropic immune functions and is critical for tolerance to self-antigen. TGFß also plays an important role in acquired tolerance to auto and alloantigens using various immunomodulatory approaches. Most importantly, ectopic expression of TGFß in pancreatic islets using transgenic systems or viral vectors proved effective in inducing tolerance to autoantigens in NOD mouse model of human T1D. However, continuous expression of this molecule is associated with massive fibrosis and long-term beta cell failure. Importantly, transient expression of TGFß in beta cells using inducible transgenic systems overcame its deleterious effects without compromising its tolerogenic function. Inasmuch as this transgenic approach is not applicable to clinical islet Tx, we envisioned that the transient display of TGFβ at protein level on the surface of islets in a clinically applicable manner may achieve tolerance without its reported complications arising from continuous expression. In limited preliminary studies, we demonstrated that the transient display of SA-TGFß on pancreatic islets was effective in overcoming rejection in a chemically induced islet Tx model. Building on these strong preliminary data, we herein propose to use SA-TGFß-engineered allogeneic islets as a means of immunomodulation to prevent graft rejection and treat diabetes in chemically and spontaneously diabetic mouse models. A series of studies will be conducted to delineate the implicated mechanisms of the tolerance. Rapid and transient display of SA-TGFß protein on pancreatic islets offers a whole new means of intervention in the areas of autoimmunity and Tx. This approach possesses the simplicity, safety, and efficacy required to make it a clinically relevant alternative that may accomplish the same goals as gene therapy in the treatment of a broad spectrum of immune-based diseases, including T1D.

描述（由申请人提供）：1型糖尿病（T1 D）仍然是超过0.9%的美国人口发病率和死亡率的主要来源，经济负担达数十亿美元。目前用于治疗T1 D的两种方法是胰岛素治疗和同种异体胰岛/胰腺移植（Tx），这两种方法都具有重大局限性。胰岛素给药不能完全预防糖尿病相关并发症。同种异体胰岛/胰腺Tx遭受排斥以及与长期使用免疫抑制药物相关的肾和胰岛毒性。因此，本基金的主要目的是建立一种新的免疫调节方案，使同种异体胰岛移植物耐受，没有持续的免疫抑制。这将通过离体工程化同种异体胰岛以在其表面瞬时展示TGF β 1，SA-TGF β 1，蛋白的新形式，并使用工程化胰岛诱导耐受性和使用啮齿动物模型治疗T1 D来实现。 T1 D和同种异体胰岛细胞破坏主要由针对独特β细胞和Tx抗原的T细胞介导。因此，控制T致病细胞的功能对于诱导对自身/同种异体抗原的耐受性和使用同种异体胰岛治疗T1 D至关重要。我们在此提出使用SA-TGF β作为免疫调节分子来实现这一目标。TGF β 1具有多效性免疫功能，对自身抗原的耐受性至关重要。TGF β 1还在使用各种免疫调节方法对自身和同种异体抗原的获得性耐受中起重要作用。最重要的是，使用转基因系统或病毒载体在胰岛中异位表达TGF β 1被证明在人T1 D的NOD小鼠模型中有效诱导对自身抗原的耐受。然而，这种分子的持续表达与大量纤维化和长期β细胞衰竭有关。重要的是，使用诱导型转基因系统在β细胞中瞬时表达TGF β克服了其有害作用，而不损害其致耐受性功能。由于这种转基因方法不适用于临床胰岛Tx，我们设想以临床适用的方式在胰岛表面上蛋白质水平瞬时展示TGFβ可以实现耐受性，而没有其报道的由连续表达引起的并发症。在有限的初步研究中，我们证明了在化学诱导的胰岛Tx模型中，SA-TGF β 1在胰岛上的瞬时展示在克服排斥方面是有效的。基于这些强有力的初步数据，我们在此提出使用SA-TGF β-工程化的同种异体胰岛作为免疫调节的手段，以预防移植排斥反应并治疗化学和自发性糖尿病小鼠模型中的糖尿病。将进行一系列的研究来阐明耐受性的相关机制。SA-TGF β 1蛋白在胰岛上的快速和瞬时显示提供了一种在自身免疫和Tx领域进行干预的全新手段。这种方法具有简单性，安全性和有效性，使其成为一种临床相关的替代方案，可以实现与基因治疗相同的目标，治疗广泛的免疫疾病，包括T1 D。