Intra-Articular Drug Delivery Modulating Immune Cells in Inflammatory Joint Disease

关节内药物递送调节炎症性关节疾病中的免疫细胞

基本信息

批准号：
10567182
负责人：
Nisarg J. Shah
金额：
$ 44.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567182
关键词：
Acids Address Adjuvant Adult Affect Antiinflammatory Effect Applications Grants Arthritis Autoantigens Autoimmune Diseases Autoimmunity Biodegradation Biodistribution Bolus Infusion CD4 Positive T Lymphocytes Cells Child Chronic Childhood Arthritis Circulation Clinical Disease Disease remission Disease-Modifying Second-Line Drugs Drug Delivery Systems Effectiveness Glycolates Goals Histopathology Human IL17 gene Immune Immune response Immune system Immunity Immunize Immunodeficient Mouse Immunosuppression Impairment Infection Infiltration Inflammation Inflammatory Inflammatory Arthritis Injections Intra-Articular Injections Joints Knowledge Malignant Neoplasms Maps Mediating Methods Methotrexate Modeling Modification Mus Orphan Ovalbumin Pathogenicity Patients Pharmaceutical Preparations Phenotype Polymers Proteins Radiolabeled Regulatory T-Lymphocyte Research Rheumatoid Arthritis Risk Safety Severity of illness Systemic disease T cell response Technology Testing Therapeutic Tissues Toxic effect Tretinoin antiarthritic agent arthropathies autoimmune arthritis autoreactive T cell autoreactivity disorder control effectiveness evaluation immune function immune modulating agents immunoregulation improved in vivo insight joint inflammation joint injury loss of function mouse model novel therapeutic intervention particle prevent receptor recruit

项目摘要

PROJECT SUMMARY Disease modifying anti-rheumatic drugs (DMARDs) have greatly improved the treatment of inflammatory joint disease but cause generalized immunosuppression and increase the risk of serious infections and cancer. The pathogenic inflammation, a hallmark of autoimmune arthritis, can largely be ascribed to a deficiency in regulatory immune function. There is a critical need for anti-arthritic agents that can operate without impairing the immune system, which could also be combined with current DMARDs in patients who struggle to achieve durable remission. Towards this goal, the objective of the grant application is to validate a new strategy of intra-articularly (IA) drug delivery of an immunomodulatory agent that could promote durable disease remission in autoimmune arthritis without causing generalized suppression of immunity. Our agent leverages pre-existing regulatory T cells (Treg), widely recognized as the primary suppressors of autoreactive T cells, to promote a disease modifying anti-inflammatory effect. Recognizing that Treg are often insufficiently recruited to the inflamed joints, display abnormal levels of inflammation-induced instability and loss of function, our approach achieves localized expansion and stabilization of joint Treg and results in reduced inflammation and systemic disease modification in affected joints of arthritic mice without causing generalized immunosuppression. Here, we will validate our approach as a therapeutic option for inflammatory arthritis. In Aim 1 we will optimize our approach such that it durably enhances the magnitude and function of Treg for modulating inflammation. In Aim 2, we will systematically validate the mechanism of action of our agent and demonstrate the enhancement of disease-relevant Treg without suppressing non-specific T cell responses. In Aim 3, we will assess the adjunctive potential of our approach with a widely used first-line DMARD to reduce disease severity in mice that show partial DMARD responsiveness and assess whether the agent is effective in the ex-vivo enhancement of Treg isolated from DMARD-treated arthritis patients. Overall, these studies will advance our long-term goal of developing our approach to correct pathogenic immune dysregulation in autoimmune disorders affecting the joint and other tissues, arising from insufficient Treg function.

项目摘要改变抗毒药（DMARD）的疾病已大大改善了炎症关节的治疗疾病但会导致广泛的免疫抑制，并增加严重感染和癌症的风险。这致病性炎症是自身免疫性关节炎的标志，在很大程度上可能归因于缺乏症调节免疫功能。对于可以在不损害的情况下操作的反关节剂的迫切需要免疫系统，也可以与努力实现的患者中的当前DMARD相结合持久的缓解。为了实现这一目标，赠款申请的目的是验证一种新的策略关节内（IA）药物输送免疫调节剂，可以促进持久疾病缓解在自身免疫性关节炎中，不会引起对免疫的普遍抑制。我们的代理商利用预先存在的调节性T细胞（TREG）被广泛认为是自动T细胞的主要抑制剂，以促进A 疾病改变抗炎作用。认识到Treg通常不足以招募到发炎的关节，表现出异常的炎症引起的不稳定和功能丧失，我们的方法实现关节treg的局部扩张和稳定，并导致炎症和全身性减少关节炎小鼠关节的疾病修饰，而不会引起普遍的免疫抑制。这里，我们将验证我们的方法作为炎症性关节炎的治疗选择。在目标1中，我们将优化我们的方法使其持久地增强了Treg调节炎症的大小和功能。目标 2，我们将系统地验证代理的作用机理，并证明与疾病相关的treg，没有抑制非特异性T细胞反应。在AIM 3中，我们将评估辅助功能通过广泛使用的一线DMARD来减少显示的小鼠疾病严重程度的潜力部分dmard的响应能力并评估代理是否有效地在Treg的外部增强中有效从DMARD治疗的关节炎患者中分离出来。总体而言，这些研究将推进我们的长期目标开发我们在自身免疫性疾病中纠正致病性免疫失调的方法关节和其他组织，由Treg功能不足引起。