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: 8833277
• 负责人: CAROLINE McPhee LEETH
• 金额: $ 14.85万
• 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/8833277
• 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; CD8B1 gene; 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; Health; Human; Human Resources; Hyperglycemia; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; 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; Outcome; Pancreas; Pathogenesis; Patients; Play; Population; Positioning Attribute; Process; Publications; Publishing; Research; Research Ethics; Research Personnel; Research Technics; Resistance; Resources; Risk; Role; Series; Staging; Surface Immunoglobulins; Systemic Lupus Erythematosus; 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; diabetes mellitus therapy; diabetes risk; homologous recombination; human disease; insulin dependent diabetes mellitus onset; knowledge base; lectures; member; mouse model; novel; novel therapeutic intervention; programs; recombinational repair; repaired; research study; response; rituximab; stem; success; symposium; therapeutic target; 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）：本申请旨在资助我对自身免疫性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。这些研究将作为我未来研究计划的基础，使我成为学术教师。作为临床DVM的初始背景为我提供了广泛的基础，在此基础上，我正在利用人类自身免疫性疾病的小鼠模型建立我的科学研究事业。我在2011年冬天顺利完成了博士学位，并继续朝着成为一名独立研究员的目标努力。在我的博士工作中研究了B淋巴细胞介导的t细胞依赖性疾病系统性红斑狼疮（SLE），我希望通过过渡到研究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。在大约一年前完成这一转变后，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了解，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自身免疫的知识，并熟悉更多的研究技术。此外，从这项工作以及未来几年R01应用的想法的进展来看，一些出版物应该是可能的。所有这些努力都将大大增加我作为独立学术教师的下一个职位的成功机会。杰克逊实验室是使用人类疾病小鼠模型进行这项研究的理想场所。该研究所拥有最先进的科学设施，以及大量知识渊博的教职员工来协助我的工作。此外，杰克逊实验室还为来自世界各地的重要外部研究人员提供演讲场所，包括每周系列讲座和年度会议。美国国立卫生研究院还批准了一个项目，对研究伦理进行持续培训。我的导师David Serreze博士是世界知名的自身免疫性糖尿病领域的高级研究员，他已经培养了许多成功的学员在学术界和工业界担任独立职位。他的实验室和资源建立良好，资金充足，他承诺支持我的努力。我的共同导师Kevin Mills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，这些著作是本提案的关键要素，并承诺以任何可能的方式帮助我实现这一申请的目标。杰克逊实验室及其工作人员将确保我得到一切必要的支持，以成功完成这项提案的科学目标，并帮助我过渡到一个独立的研究人员。人类和NOD小鼠模型中的T1D最终都是由T细胞介导的自身免疫破坏产生胰岛素的胰腺引起的。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t细胞反应中起关键作用。本应用的科学目标是寻求优化b淋巴细胞靶向治疗T1D的干预措施。几种不同的b淋巴细胞定向疗法在NOD小鼠疾病发展的早期阶段成功地减缓了T1D的进展，包括rituxamib样抗cd20抗体和BAFF阻断剂。然而，目前只有在表现出持续高水平的？细胞破坏，如循环自身抗体的存在。因此，临床可翻译的T1D干预措施必须在开始时有效