Islet growth in NOD mice tolerant to autoimmune diabetes

耐自身免疫性糖尿病的 NOD 小鼠的胰岛生长

• 批准号: 6827263
• 负责人: VIRGINIA E. PAPAIOANNOU
• 金额: $ 20.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827263
• 关键词: CD3 molecule; NOD mouse; apoptosis; cell differentiation; cell proliferation; embryonic stem cell; genetically modified animals; green fluorescent proteins; hepatocyte growth factor; immune tolerance /unresponsiveness; immunocytochemistry; insulin dependent diabetes mellitus; monoclonal antibody; pancreatic islets; peptide hormone analog; stem cell transplantation

DESCRIPTION (provided by applicant): The goal of this proposal is to reverse Type 1 diabetes by inducing tolerance to the autoimmune process and replenishing lost islet cells from precursors. Previous clinical studies by Dr. Herold have shown that treatment with an anti-CD3 monoclonal antibody can prevent the loss of insulin production for up to 2 years after onset of diabetes, and preclinical studies suggest that anti-CD3 mAb induces tolerance to the autoimmune disease. However, to establish normal metabolic control, this therapy must be combined with a means of replenishing lost islet tissue. We will test whether, after induction of immunologic tolerance, islets will regenerate, can be stimulated to grow, or whether embryonic stem cells from the pancreatic anlagen may be used to replenish the lost beta cell mass. The proposal will develop a partnership between Dr. Kevan Herold, whose work has been in the immunology and immunotherapy of Type 1 diabetes and Dr. Virginia Papaioannou, who is an expert in the field of developmental biology but who has not previously worked in the field of diabetes. We will first determine whether induction of immune tolerance to autoimmune diabetes in the NOD mouse results in islet cell proliferation. Studies in this aim will include immunohistochemical and molecular analyses of developing insulin+ cells. We will test whether islet cell regeneration can be stimulated using exendin-4 and hepatocyte growth factor which can stimulate beta cell development in non-immune mediated animal models of insulin deficiency. We will test whether stem cells can be grown into islets that can correct diabetes by transplanting pancreatic anlagen from normal MHC matched mice into diabetic NOD mice treated with anti-CD3 mAb. Differentiation into mature pancreatic cells will be studied, and a fluorochrome tagged donor will enable us to identify the source of any newly differentiated insulin+ cell. By comparing this process in the presence or absence of anti-CD3 mAb treatment with hyper or euglycemia, we will be able to obtain additional information including expression of disease relevant islet antigens, and the effects of insulin and glucose on differentiation of islet cells. Drs. Herold and Papaioannou will collaborate closely particularly in the molecular and stem cell studies proposed. By combining the expertise of the two Pl's to address the problems of islet autoimmunity and beta cell deficiency our proposal will test a combination strategy that may be useful in patients.

描述（由申请人提供）： 该提案的目标是通过诱导对自身免疫过程的耐受性和从前体细胞中补充丢失的胰岛细胞来逆转1型糖尿病。赫罗尔德博士先前的临床研究表明，抗CD 3单克隆抗体治疗可以防止糖尿病发作后长达2年的胰岛素产生丧失，临床前研究表明，抗CD 3 mAb诱导对自身免疫性疾病的耐受性。然而，为了建立正常的代谢控制，这种治疗必须与补充失去的胰岛组织的方法相结合。我们将测试在诱导免疫耐受后，胰岛是否会再生，是否可以刺激生长，或者是否可以使用来自胰腺原基的胚胎干细胞来补充丢失的β细胞群。该提案将在Kevan赫罗尔德博士和Virginia Papaioannou博士之间建立合作伙伴关系，Kevan Herold博士一直致力于1型糖尿病的免疫学和免疫治疗，Virginia Papaioannou博士是发育生物学领域的专家，但此前从未在糖尿病领域工作过。我们将首先确定在NOD小鼠中诱导对自身免疫性糖尿病的免疫耐受是否导致胰岛细胞增殖。这方面的研究将包括对发育中的胰岛素+细胞进行免疫组织化学和分子分析。我们将测试是否可以使用exendin-4和肝细胞生长因子来刺激胰岛细胞再生，所述exendin-4和肝细胞生长因子可以在胰岛素缺乏的非免疫介导的动物模型中刺激β细胞发育。我们将测试干细胞是否可以生长成胰岛，通过将来自正常MHC匹配小鼠的胰腺原基移植到用抗CD 3 mAb治疗的糖尿病NOD小鼠中来纠正糖尿病。分化成成熟的胰腺细胞将被研究，荧光标记的供体将使我们能够识别任何新分化的胰岛素+细胞的来源。通过比较在存在或不存在抗CD 3 mAb治疗的情况下与高或正常胰岛素的该过程，我们将能够获得额外的信息，包括疾病相关胰岛抗原的表达，以及胰岛素和葡萄糖对胰岛细胞分化的影响。赫罗尔德博士和Papaioannou将密切合作，特别是在分子和干细胞研究提出。通过结合两个PI的专业知识来解决胰岛自身免疫和β细胞缺陷的问题，我们的建议将测试可能对患者有用的组合策略。