Use of beta cell epitopes in preventing type 1 diabetes in humanized mice

使用 β 细胞表位预防人源化小鼠 1 型糖尿病

• 批准号: 8779407
• 负责人: Jennifer Schloss
• 金额: $ 3.93万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-16 至 2019-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779407
• 关键词: Acceleration; Adjuvant; Advanced Development; Animals; Antibodies; Antigens; Autoimmune Diseases; Beta Cell; CD8B1 gene; Catalytic Domain; Cells; Clinical; DEC-205 receptor; Dendritic Cells; Development; Diabetes Mellitus; Diabetes prevention; Disease; Epitope Mapping; Epitopes; Future; HLA A*0201 antigen; HLA-B Antigens; HLA-B27 Antigen; Histocompatibility Antigens Class I; Human; ITGAX gene; Inbred NOD Mice; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Laboratories; Link; MHC Class I Genes; Maps; Mediating; Methods; Modeling; Mus; Myelogenous; Pancreas; Patients; Peptides; Population; Prevention; Proteins; Reagent; Splenocyte; T-Lymphocyte; Transgenic Mice; Transgenic Organisms; Translating; Translations; Veins; Work; base; clinically relevant; early onset; glucose-6-phosphatase; in vivo; insulin dependent diabetes mellitus onset; islet; member; mouse model; prevent; promoter; public health relevance; rare variant; research clinical testing

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the insulin-producing ¿ cells in the pancreatic islets. Several T1D-associated class I MHCs have been identified, including HLA-A*0201, expressed by many T1D patients; ¿ cell epitopes restricted to this MHC have been identified as well. We hypothesize that these ¿ cell epitopes may be utilized as part of immunomodulatory therapies to prevent the onset of T1D. This may be done by utilizing the dendritic cell (DC) endocytic receptorDEC-205. In the absence of adjuvant, epitopes delivered via DEC-205 are presented to T cells in a tolerogenic manner, resulting in T cell tolerance towards those epitopes. Our laboratory has shown that when murine ¿ cell epitopes linked to anti-murine DEC-205 are delivered to DCs in vivo, T cells specific for those epitopes are deleted in non-obese diabetic (NOD) mice. We will further these studies in humanized mouse models. Importantly, while only a subset of murine DCs expresses DEC-205, it is present on all human myeloid DCs; our model replicates the human case via expression of human DEC-205 on all murine myeloid DCs. We hypothesize that, as with anti-murine DEC-205 treatments, the delivery of murine ¿ cell epitopes via antibodies against human DEC-205 will also induce T cell tolerance. Previous studies have also shown that simultaneous delivery of several HLA-A*0201-restricted ¿ cell epitopes, chemically linked to splenocytes, to HLA-A*0201-transgenic NOD mice prevented the onset of diabetes. To develop more clinically relevant reagents, we will simultaneously deliver these epitopes to NOD mice transgenic for both human DEC-205 and HLA-A*0201; we expect the induction of T cell tolerance towards these epitopes and prevention of T1D. This has the potential to aid the many T1D patients who express HLA-A*0201. However, HLA-A*0201 is not expressed by all T1Dpatients. To develop treatments for these patients, other T1D-associated class I MHCs should be considered, including the early onset-associated HLA-B*3906. While HLA-B*3906 is itself a rare allele, we have shown it to be a member of the HLA-B27 super type, whose members are expressed by 28% of the population. Studying HLA-B*3906 has the potential to have a large impact as peptides presented by one super type member are often capable of being presented by another. Our preliminary studies suggest that expression of HLA-B*3906in NOD mice results in the acceleration of T1D. To further examine the effect of HLA-B*3906 on T1D, we will also determine the effect of HLA-B*3906 on T1D incidence in NOD mice lacking murine class I MHC. A similar model has been used to identify HLA-A*0201-restricted ¿ cell epitopes, a method we will apply to HLA-B*3906.To do so, we will map potential epitopes from both human and murine ¿ cell antigens. These epitopes could then be used in future immunomodulatory therapies.

描述（由应用程序提供）：1型糖尿病（T1D）是由T细胞介导的胰岛胰岛中产生胰岛素的细胞破坏引起的自身免疫性疾病。已经确定了几个与T1D相关的I类MHC，包括许多T1D患者表达的HLA-A*0201；也已经鉴定出限于该MHC的细胞表位。我们假设这些细胞表位可以用作免疫调节疗法的一部分，以防止T1D发作。这可以通过利用树突状细胞（DC）内吞营养受体-205来完成。在没有可调节的情况下，通过DEC-205传递的表位以耐受性方式呈现给T细胞，从而导致T细胞对这些表位的耐受性。我们的实验室表明，当鼠 - 与抗毛线DEC-205相关的细胞表位被输送到体内DC时，在非肥胖糖尿病（NOD）小鼠中删除了特异性表位的T细胞。我们将在人性化小鼠模型中进一步研究这些研究。重要的是，虽然只有一部分鼠DCS表示Dec-205，但它存在于所有人类髓样DC上。我们的模型通过在所有鼠髓样DC上的人类DEC-205的表达来复制人类病例。我们假设，与抗毛线DEC-205治疗一样，通过针对人DEC-205的抗体递送鼠 - 细胞表位也将诱导T细胞耐受性。先前的研究还表明，几种HLA-A*0201限制的细胞表位，与脾细胞化学相关的细胞表位，与HLA-A*0201-Transgenic NOD小鼠相关，从而阻止了糖尿病的发作。为了开发更多临床相关的试剂，我们只需将这些表位提供给人类DEC-205和HLA-A*0201的转基因小鼠转基因；我们期望T细胞耐受性诱导这些表位和预防T1D。这有可能帮助许多表达HLA-A*0201的T1D患者。但是，HLA-A*0201并未由所有T1DPatients表示。为了开发这些患者的治疗方法，应考虑其他与T1D相关的I类MHC，包括早期发作相关的HLA-B*3906。虽然HLA-B*3906本身就是罕见的等位基因，但我们已经证明它是HLA-B27 Super Type的成员，其成员由28％的人口表示。研究HLA-B*3906有可能产生很大的影响，因为一个超级型成员的宠物通常能够由另一个成员提出。我们的初步研究表明，hla-b*3906在点头小鼠的表达导致T1D加速。为了进一步研究HLA-B*3906对T1D的影响，我们还将确定HLA-B*3906对缺乏Murine I类MHC的NOD小鼠T1D入射的影响。已经使用类似的模型来识别HLA-A*0201限制的细胞表位，我们将适用于HLA-B*3906。为此，我们将绘制人类和鼠类细胞抗原的潜在表位。然后可以将这些表位用于将来的免疫调节疗法中。