Optimizing B-lymphocyte Therapeutic Targeting Strategies in Autoimmune Diabetes

优化自身免疫性糖尿病的 B 淋巴细胞治疗靶向策略

• 批准号: 9203623
• 负责人: CAROLINE McPhee LEETH
• 金额: $ 15.63万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203623
• 关键词: Academia; Activated B-Lymphocyte; Address; Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Apoptotic; Area; Attenuated; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Automobile Driving; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell membrane; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; DNA Double Strand Break; DNA Repair Inhibition; Data; Development; Disease; Disease Progression; Doctor of Philosophy; Effectiveness; Elements; Ensure; Epitopes; Faculty; Failure; Funding; Future; Goals; Human; Human Resources; Hyperglycemia; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Immunologics; Inbred NOD Mice; Industry; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Islets of Langerhans; Knowledge; Laboratories; Life; Location; Lymphocyte Subset; Lymphoma; MS4A1 gene; Mature B-Lymphocyte; Mediating; Mentors; Monoclonal Antibody Therapy; Pancreas; Pathogenesis; Pathogenicity; Patients; Pharmacology; Play; Population; Positioning Attribute; Process; Publications; Publishing; Research; Research Ethics; Research Personnel; Research Technics; Resistance; Resources; Risk; Role; Series; Structure of beta Cell of islet; Surface Immunoglobulins; Systemic Lupus Erythematosus; Systemic disease; T cell response; T-Lymphocyte; Testing; The Jackson Laboratory; Therapeutic; Therapeutic Intervention; Training; United States National Institutes of Health; Work; activation-induced cytidine deaminase; apoptosis in lymphocytes; attenuation; base; career; clinically relevant; clinically translatable; diabetes mellitus therapy; diabetes risk; diabetogenic; experimental study; homologous recombination; human disease; insulin dependent diabetes mellitus onset; knowledge base; lectures; member; mouse model; novel; novel therapeutic intervention; programs; public health relevance; recombinational repair; repaired; response; rituximab; stem; success; symposium; targeted treatment; therapeutic target; therapy outcome; tool; tositumomab

DESCRIPTION (provided by applicant): This application seeks funding for my scientific investigations into the pathogenesis of and possible clinically translatable interventions for autoimmune type 1 diabetes (T1D). These studies will serve as a basis for my future research program, positioning me for an academic faculty position. Having an initial background as a clinical DVM provides me a broad base on which I am building my scientific research career using mouse models of human autoimmune diseases. I successfully completed my Ph.D. in the winter of 2011 and am continuing to work towards my goal of becoming an independent researcher. Having studied the B-lymphocyte mediated, T-cell dependent disease systemic lupus erythematosus (SLE) for my Ph.D. work, I wished to broaden my autoimmunity knowledge base by transitioning to investigating the T-cell mediated, B lymphocyte dependent disease, T1D. Having made this transition approximately a year ago, my immediate goals are to continue building upon my knowledge of autoimmune disease pathogenesis as well as gain new tools for this area of research. Funding of this proposal would allow me to expand my knowledge of autoimmunity as well as familiarize myself with additional research techniques. In addition, several publications should be possible from this work as well as the progression of ideas for an R01 application in the coming years. All of these efforts enabled with this proposal will greatly increase my chances of success in my next position as an independent academic faculty member. The Jackson Laboratory is an ideal location to perform the studies in this proposal using mouse models of human disease. The institute has state of the art scientific facilities as well as a wealth of exceptionally knowledgeable faculty and staff to assist me with my work. In addition, The Jackson Laboratory provides venues in which important outside researchers from around the world come to speak including a weekly lecture series as well as annual conferences. An NIH-approved program is also in place for continued training in research ethics. My mentor, Dr. David Serreze, is a world-renowned senior researcher in the field of autoimmune diabetes and has graduated many successful trainees to independent positions in both academia and industry. His laboratory and resources are well established and well funded and he is committed to supporting my endeavors. My co-mentor Dr. Kevin Mills is also a leader in his field, having recently published important works on immunological areas key to elements of this proposal and has pledged to assist me in any way possible in pursuing the aims in this application. The Jackson Laboratory and its personnel will ensure I receive all the support necessary to successfully complete the scientific goals of this proposal as well as aid in my transition to an independent researcher. T1D in both humans and the NOD mouse model ultimately results from T cell mediated autoimmune destruction of insulin producing pancreatic ? cells. However, in NOD mice, and also likely in humans, B- lymphocytes play a key role in driving diabetogenic T-cell responses. The scientific goals of this application seek to optimize B-lymphocyte targeted therapeutic interventions for T1D. Several different B-lymphocyte directed therapies have been successful at attenuating progression to T1D when initiated at early stages of disease development in NOD mice including the rituxamib-like anti-CD20 antibody and BAFF blockade. However, humans at high future risk for T1D can currently only be identified after manifesting signs of ongoing high levels of ? cell destruction such as the presence of circulating autoantibodies. Thus, clinically translatable T1D interventions must be effective when initiated at late stages of disease development. In recent onset human T1D patients, transient therapy with the CD20 specific rituximab antibody provided only marginally effective at clinical disease attenuation. A possible explanation for this weak effect may stem from previous findings by our group that some B-lymphocyte populations in NOD mice, including those infiltrating pancreatic islets, are resistant to deletion by rituximab-like anti-CD20 therapy. One goal in this proposal is to understand to what extent B-lymphocyte subpopulations that are resistant to anti-CD20 mediated deletion contribute to various stages of T1D progression, and to investigate alternative therapeutic approaches to repress these cells. Another goal is to determine the importance of B-lymphocyte affinity maturation for antigen in T1D pathogenesis and includes the testing of a novel therapeutic approach borrowed from the lymphoma field that targets this process. When initiated at late stages of T1D development, the best therapeutic outcomes may be obtained with combination therapies, and the experiments in this proposal will address this possibility. The overall importance of this proposal lies in the identification of B-lymphocyte directed T1D therapies most effective at late stages of disease development as this information will be of highest clinically translatable relevance.

描述（由申请人提供）：本申请旨在为我对自身免疫性1型糖尿病（T1D）的发病机制和可能的临床可翻译干预措施的科学研究提供资金。这些研究将作为我未来研究计划的基础，为我定位学术教师的位置。作为临床DVM的初始背景为我提供了一个广泛的基础，我正在使用人类自身免疫性疾病的小鼠模型建立我的科学研究生涯。我成功地完成了我的博士学位。2011年冬天，我继续朝着成为一名独立研究员的目标努力。在攻读博士学位期间，我研究了B淋巴细胞介导的T细胞依赖性疾病系统性红斑狼疮（SLE）。在工作中，我希望通过研究T细胞介导的B淋巴细胞依赖性疾病T1D来拓宽我的自身免疫知识基础。大约一年前完成了这一转变，我的近期目标是继续建立我对自身免疫性疾病发病机制的认识，并为这一研究领域获得新的工具。这项提案的资助将使我能够扩大我对自身免疫的知识，并熟悉其他研究技术。此外，几个出版物应该是可能的，从这项工作以及在未来几年的R01应用的想法的进展。所有这些努力使这个建议将大大增加我的成功的机会，在我的下一个位置作为一个独立的学术教员。杰克逊实验室是使用人类疾病小鼠模型进行本提案中研究的理想场所。该研究所拥有最先进的科学设施，以及丰富的知识渊博的教师和工作人员，以协助我的工作。此外，杰克逊实验室提供场地，其中来自世界各地的重要外部研究人员来发言，包括每周讲座系列以及年度会议。一个NIH批准的项目也在进行研究伦理的持续培训。我的导师，大卫Serreze博士，是一个世界知名的自身免疫性糖尿病领域的高级研究员，并毕业了许多成功的学员在学术界和工业界的独立职位。他的实验室和资源都很完善，资金充足，他致力于支持我的努力。我的共同导师凯文米尔斯博士也是他所在领域的领导者，他最近发表了关于免疫学领域的重要著作，这些著作对本提案的要素至关重要，他承诺将以任何可能的方式帮助我实现本申请的目标。杰克逊实验室及其工作人员将确保我获得成功完成本提案的科学目标所需的一切支持，并帮助我过渡到独立研究人员。人类和NOD小鼠模型中的T1D最终是由T细胞介导的自身免疫性破坏产生胰岛素的胰腺？细胞然而，在NOD小鼠中，也可能在人类中，B淋巴细胞在驱动致糖尿病性T细胞应答中起关键作用。本申请的科学目标是优化T1D的B淋巴细胞靶向治疗干预。在NOD小鼠疾病发展的早期阶段启动时，几种不同的B淋巴细胞定向疗法已成功地减弱了向T1D的进展，包括利妥昔单抗样抗CD20抗体和BAFF阻断。然而，人类在未来高风险的T1D目前只能确定后，表现出持续高水平的迹象？细胞破坏，如循环自身抗体的存在。因此，临床上可翻译的T1D干预措施在开始时必须有效， 疾病发展的晚期阶段。在最近发病的人类T1 D患者中，使用CD 20特异性利妥昔单抗抗体的短暂治疗在临床疾病减轻方面仅具有轻微效果。这种弱效应的一个可能解释可能源于我们小组先前的发现，即NOD小鼠中的一些B淋巴细胞群，包括浸润胰岛的B淋巴细胞群，对利妥昔单抗样抗CD20治疗的缺失具有抗性。该提案的一个目标是 了解对抗CD20介导的缺失具有抗性的B淋巴细胞亚群在多大程度上促进了T1D进展的各个阶段，并研究抑制这些细胞的替代治疗方法。另一个目标是确定T1D发病机制中抗原的B淋巴细胞亲和力成熟的重要性，并包括测试从淋巴瘤领域借用的靶向该过程的新治疗方法。当在T1D发展的晚期阶段开始时，最好的治疗结果可能是通过联合治疗获得的，本提案中的实验将解决这种可能性。该建议的总体重要性在于确定在疾病发展的晚期阶段最有效的B淋巴细胞定向T1D疗法，因为该信息将具有最高的临床可转化相关性。