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放在两个方面。第一个是开发创新的治疗策略，在初级临床项目中，关于治疗对1型糖尿病(T1D)中人类白细胞抗原-多肽相互作用的影响的机制，以及在替代临床项目中，关于重点预防类风湿性关节炎(RA)的临床明显疾病的发病。合作项目的研究旨在显著提高我们对人类疾病视神经脊髓炎恶化和缓解的特定免疫机制的了解，在这种疾病中，致病过程是由B和T细胞对明确定义的自身抗原水通道蛋白4的识别推动的。此外，由于我们最近对T1D和RA抗原特异性反应的了解有所增加，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果，还影响相关的抗原特异性反应。为了达到上述目标，科罗拉多州ACE的研究人员提出了三个具体目标：具体目标1：评估旨在中断/调节MHC第二类分子与多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治疗策略的能力。具体目标#2：开发、测试和评估侧重于预防极高风险受试者的类风湿性关节炎和其他自身免疫性疾病的临床发病的治疗策略的免疫调节效果和临床益处。具体目标#3：了解与靶向治疗的临床反应和临床状态变化相关的B和T细胞自身抗原特异性反应的变化。最后，科罗拉多州的ACE研究人员拥有庞大多样的临床人群，以高度协作的方式进行成功的临床研究和试验的强大历史，以及在临床表型和生物标记物开发方面的广泛经验，科罗拉多州ACE研究人员将为新成立的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.