B-lymphocyte Targeting Therapies for Autoimmune Diabetes

B 淋巴细胞靶向治疗自身免疫性糖尿病

• 批准号: 10609074
• 负责人: David V Serreze
• 金额: $ 54.37万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609074
• 关键词: Ablation; Acceleration; Address; Antibodies; Antigen-Presenting Cells; Attenuated; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diabetes; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Beta Cell; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell membrane; Cells; Characteristics; Clinical Trials; Data; Defect; Development; Disease; Finding by Cause; Future; Genes; Genetic; Goals; Human; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Immunosuppression; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Intervention; Islets of Langerhans; Life; Lymphocyte Depletion; MS4A1 gene; Mediating; Multiple Sclerosis; Mus; Neuritis; Neurons; Onset of illness; Pancreas; Pathogenicity; Pathology; Patients; Pharmacologic Substance; Phenotype; Play; Population; Predisposition; Process; Public Health; Reagent; Role; Specificity; Structure of beta Cell of islet; Surface Immunoglobulins; Syndrome; T cell response; T-Cell Activation; T-Lymphocyte; Testing; anti-CD20; autoimmune pathogenesis; autoreactivity; clinically relevant; diabetes risk; diabetogenic; genetic variant; insight; insulin dependent diabetes mellitus onset; interest; mouse model; peripherin; protective effect; receptor; response; rituximab; targeted treatment

PROJECT SUMMARY While the autoimmune destruction of pancreatic ß-cells causing type 1 diabetes (T1D) is ultimately a T-cell mediated process, it is clear in the NOD mouse model and also likely humans, that B-lymphocytes play an additional key pathogenic role. B-lymphocytes likely contribute to T1D by being the subset of APC most efficiently supporting pathogenic T-cell activation. This is due to the presence of B-lymphocytes expressing immunoglobulin (Ig) molecules that can efficiently capture and internalize ß-cell autoantigens. Thus, defects in mechanisms normally blocking the development or activity of autoreactive B- as well as T-lymphocytes contribute to T1D. Due to their role in supporting pathogenic T-cell responses there has been considerable interest in developing possible B-lymphocyte directed T1D interventions. Hence, the central hypothesis of this proposal is that gaining an increased understanding of the developmental and functional activity basis of T1D relevant B-lymphocytes in NOD mice could be of significance in identifying a means by which they could be effectively targeted. In this regards, current data indicate BAFF blockade may be a more effective B- lymphocyte directed T1D intervention than anti-CD20 treatment. Preliminary data now indicate a hypomorphic Ephb2 allelic variant may represent a T1D susceptibility (Idd) gene in NOD mice acting at the level of B- lymphocytes. Transgenically elevating Ephb2 expression inhibits T1D development through a B-lymphocyte dependent process. Aim 1 will address the currently unknown question if NOD B-lymphocytes with elevated Ephb2 expression have lost an ability to functionally activate diabetogenic T-cells, or alternatively have gained a capacity to functionally suppress such pathogenic effectors. We also previously found that a genetic and pharmaceutical approach inhibiting the ability of B-lymphocytes to undergo the processes of Ig somatic hypermutation (SHM) and class switch recombination (CSR) inhibits T1D development in NOD mice. Such T1D protection resulted from B-lymphocytes unable to undergo SHM and CSR converting to a regulatory phenotype (Breg) that inhibit pathogenic T-cells through increased activity of the immunosuppressive CD39/CD73 ecto-enzyme axis. More recent studies unexpectedly indicate ablation of the CD39 gene inhibits T1D development in NOD mice, and this is associated with a respective proportional increase and decrease in total B- and T-lymphocytes. Thus, Aim 2 is to determine if ablation of CD39 inhibits T1D development in NOD mice by expanding B-lymphocytes with a capacity to suppress pathogenic T-cell responses. We have also found T1D onset is accelerated in NOD mice with B-lymphocytes transgenically expressing an Ig specificity recognizing the peripherin molecule present in both pancreatic islets and neurons (NOD-PerIg mice), but this strain can also develop a potential multiple sclerosis (MS) relevant neurtitis syndrome. Aim 3 will determine the potential overlap in B-lymphocyte driven T-cell populations mediating T1D and neuritis development in NOD-PerIg mice, and assess if either of these pathologies can be attenuated by BAFF blockade.

项目摘要 虽然导致1型糖尿病（T1 D）的胰腺β细胞的自身免疫性破坏最终是T细胞 在NOD小鼠模型和可能的人类中，B淋巴细胞在介导的过程中起着重要作用， 额外的关键致病作用。B淋巴细胞可能通过作为APC的亚群而导致T1 D， 有效支持致病性T细胞活化。这是由于B淋巴细胞表达 免疫球蛋白（IG）分子，其可以有效地捕获和内化β细胞自身抗原。因此， 通常阻断自身反应性B淋巴细胞和T淋巴细胞的发育或活性的机制 有助于T1 D。由于它们在支持致病性T细胞应答中的作用， 有兴趣开发可能的B淋巴细胞导向的T1 D干预措施。因此，这个问题的核心假设 建议是，增加对T1 D的发育和功能活动基础的了解， NOD小鼠中的相关B淋巴细胞可能在确定它们可以被 有效针对。在这方面，目前的数据表明BAFF阻断可能是更有效的B- 淋巴细胞定向的T1 D干预比抗CD 20治疗更有效。初步数据显示 Ephb 2等位基因变异体可能代表NOD小鼠中在B水平起作用的T1 D易感性（Idd）基因。 淋巴细胞转基因提高Ephb 2表达通过B淋巴细胞抑制T1 D发展 依赖过程。目的1将解决目前未知的问题，如果NOD B淋巴细胞升高， Ephb 2表达丧失了功能性激活致糖尿病T细胞的能力，或者获得了 在功能上抑制这种致病效应物的能力。我们以前也发现， 抑制B淋巴细胞经历IG体细胞过程的能力的药物方法 超突变（SHM）和类别转换重组（CSR）抑制NOD小鼠中的T1 D发展。等 T1 D保护是由于B淋巴细胞不能进行SHM和CSR转化为调节性的 表型（布雷格），其通过增加免疫抑制因子的活性来抑制致病性T细胞。 CD 39/CD 73胞外酶轴。最近的研究意外地表明，去除CD 39基因抑制了 NOD小鼠中的T1 D发展，这与NOD小鼠中T1 D的相应比例增加和减少有关。 总B和T淋巴细胞。因此，目的2是确定CD 39的消融是否抑制NOD中的T1 D发展 通过扩增具有抑制致病性T细胞反应能力的B淋巴细胞对小鼠进行免疫。我们还 发现在具有转基因表达IG特异性的B淋巴细胞的NOD小鼠中T1 D发作加速 识别存在于胰岛和神经元中的外周蛋白分子（NOD-PerIg小鼠），但这 菌株也可发展成潜在多发性硬化（MS）相关神经炎综合征。目标3将决定 B淋巴细胞驱动的T细胞群介导T1 D和神经炎发展的潜在重叠， NOD-PerIg小鼠，并评估这些病理学中的任一种是否可以通过BAFF阻断而减弱。