Colorado Autoimmunity Center of Excellence

描述（由申请人提供）：科罗拉多大学自身免疫卓越中心（科罗拉多ACE）的成员提出了两个临床项目和一个合作项目。整个中心的建设重点是两个领域。第一个是创新治疗策略的开发，在主要临床项目中关于治疗剂对1型糖尿病（T1 D）中HLA-肽相互作用的作用机制，以及在替代临床项目中关于预防风湿性关节炎（RA）临床明显疾病发作的重点。合作项目中的研究旨在大幅增加我们对人类疾病（视神经肌萎缩症）恶化和缓解的特定免疫机制的理解，其中致病过程由B和T细胞识别明确的自身抗原水通道蛋白4驱动。此外，由于最近我们对T1 D和RA抗原特异性反应的理解有所增加，我们还将能够在临床项目中确定治疗干预如何不仅影响临床结局，而且影响相关的抗原特异性反应。为了实现所述目标，科罗拉多ACE的研究者提出了三个具体目标：具体目标#1：评价设计用于中断/调节MHC II类分子与肽的相互作用以改善器官特异性和非特异性自身免疫的新型治疗策略的能力。具体目标#2：开发、测试和评估治疗策略的免疫调节作用和临床获益，重点是预防极高危受试者中类风湿性关节炎和其他自身免疫性疾病的临床发作。具体目标#3：了解B和T细胞自身抗原特异性反应的改变，这些改变与靶向治疗的临床反应和临床状态的变化相关。最后，科罗拉多ACE研究者拥有大量不同的临床人群、以高度合作的方式进行的成功临床研究和试验的强大历史以及在临床表型和生物标志物开发方面的广泛经验，将为新成立的ACE联盟提供重要资源。

DESCRIPTION (provided by applicant): The members of the University of Colorado Autoimmunity Center of Excellence (Colorado ACE) are proposing two Clinical Projects and one Collaborative Project. The overall Center has been constructed with a focus on two areas. The first is the development of innovative therapeutic strategies, in the Primary Clinical Project with regard to the mechanism of effect of the therapeutic on HLA-peptide interaction in Type 1 Diabetes (T1D) and in the Alternate Clinical Project with regard to the focus on prevention of the onset of clinically apparent disease in Rheumatoid Arthritis (RA). Studies in the Collaborative Project are intended to substantially increase our understanding of the specific immune mechanisms underlying exacerbation and remission of a human disease, neuromyelitis optica, in which the pathogenic process is driven by B and T cell recognition of a well-defined autoantigen, aquaporin 4. In addition, because of recent increases in our understanding of antigen-specific responses in T1D and RA, we will also be able to determine in the Clinical Projects how therapeutic intervention not only affects clinical outcomes but also relevant antigen-specific responses. To address the stated goals, the investigators of the Colorado ACE propose three Specific Aims: Specific Aim #1: Evaluate the ability of novel therapeutic strategies designed to interrupt/modulate MHC Class II molecular interactions with peptides to lead to amelioration of organ-specific and non-specific autoimmunity. Specific Aim #2: Develop, test and evaluate the immunomodulatory effects and clinical benefit of treatment strategies that are focused on prevention of the clinical onset of rheumatoid arthritis and other autoimmune diseases in extraordinarily high-risk subjects. Specific Aim #3: Develop an understanding of the alterations to B and T cell autoantigen-specific responses that are associated with clinical responses to targeted therapeutics and change in clinical status. Finally, with a large and varied clinical population, a strong history of successful clinical studies and trials performed in a highly collaborative manner, and broad experience in clinical phenotyping and biomarker development, the Colorado ACE investigators will provide an important resource to the newly constituted ACE Consortium.