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Developing co-stimulatory blockade as a therapeutic strategy for Duchenne muscular dystrophy

开发共刺激阻滞作为杜氏肌营养不良症的治疗策略

基本信息

批准号：
10016862
负责人：
JAMES G TIDBALL
金额：
$ 34.13万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016862
关键词：
Affect Animals Autopsy Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CTLA4 gene Cell physiology Cells Chimeric Proteins Communication Disease Duchenne muscular dystrophy Endothelial Cells Environment Equilibrium Extravasation Fatigue Fibrosis Glucocorticoids Goals Growth Health Immune Immune response Immune system Immunobiology Immunomodulators Immunosuppressive Agents In Vitro Inflammation Injury Intervention Investigation Knowledge Leukocytes Long-Term Effects Lymphoid Cell Mediating Modeling Motor Mus Muscle Muscle Fibers Muscular Atrophy Muscular Dystrophies Myeloid Cells Myopathy Natural regeneration Outcome Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Prednisone Process Production Recombinant Fusion Proteins Regulatory T-Lymphocyte Research Role Safety Signal Transduction Skeletal Muscle T-Cell Activation Testing Therapeutic Tissues Treatment Efficacy Untranslated Regions Utrophin Wasting Syndrome clinical practice cytokine cytotoxicity human disease immune function improved functioning in vivo macrophage mdx mouse mouse model muscle necrosis muscle regeneration mutant novel therapeutic intervention preclinical study prednisolone regenerative safety testing standard of care treatment effect

项目摘要

Project summary. The long-term goal of our research is to develop better strategies to manipulate interactions between dystrophic muscle and the immune system, so that the pathology of Duchenne muscular dystrophy (DMD) can be reduced. As our knowledge of the interactions between the immune system and dystrophic muscle has grown, several distinct mechanisms through which immune cells promote damage of dystrophic muscle have been identified. However, we have also learned that specific populations of immune cells, including some macrophage subpopulations and regulatory T-cells, promote muscle growth and regeneration in muscular dystrophy. Because the activation, phenotype and function of immune cells that affect muscular dystrophy are strongly influenced by costimulatory signals that are exchanged between myeloid cells and lymphoid cells, interventions that target costimulatory pathways have the capacity to influence the balance between detrimental and pro-regenerative processes that are mediated by immune cells in dystrophic muscle. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a particularly important costimulatory molecule that influences interactions between immune cells. Manipulation of CTLA4 availability to mediate signaling between myeloid and lymphoid cells greatly influences the magnitude and quality of the immune response to diseased tissue. Our preliminary findings support the hypothesis that administration of a recombinant fusion protein containing CTLA4 profoundly influences the immune response to dystrophic muscle and reduces muscle damage. In the investigation proposed here, we will test that hypothesis, determine the mechanisms through which CTLA4-mediated interventions affect muscular dystrophy and evaluate the safety and efficacy of long- term administration of exogenous CTLA4 in the mdx mouse model of DMD. Aim 1. Test the hypothesis that treatments with CTLA4-immunoglobin fusion protein (CTLA4-Ig) produce long- term reductions in muscle pathology and improve function in mouse models of DMD. Aim 2. Test the hypothesis that CTLA4-Ig acts on both lymphoid and myeloid cells to reduce muscle injury and inflammation and promote a pro-regenerative environment in dystrophic muscle. Aim 3. Assess safety and long-term effects of CTLA4-Ig administration on immune cell function. Together, these findings can enable us to determine whether CTLA4-Ig, a drug that is safe and efficacious for the treatment of other human diseases, can provide a successful, new strategy for treating DMD.

项目摘要。我们研究的长期目标是开发更好的策略来操纵营养不良的肌肉和免疫系统，使杜氏肌营养不良症（DMD）的病理，随着我们对免疫系统和营养不良肌肉之间相互作用的了解，生长，免疫细胞通过几种不同的机制促进营养不良肌肉的损伤，然而，我们也了解到，特定的免疫细胞群，包括一些巨噬细胞亚群和调节性T细胞，促进肌肉生长和肌肉再生，因为影响肌营养不良症的免疫细胞的激活、表型和功能是由免疫细胞的免疫反应引起的。受骨髓细胞和淋巴细胞之间交换的共刺激信号的强烈影响，靶向共刺激通路的干预有能力影响在营养不良的肌肉中由免疫细胞介导的有害的和促进再生的过程。细胞毒性T淋巴细胞相关蛋白4（CTLA 4）是一种特别重要的共刺激分子，影响免疫细胞之间的相互作用。骨髓和淋巴细胞极大地影响了对疾病的免疫应答的程度和质量。我们的初步研究结果支持了这样的假设，即重组融合蛋白的给药含有CTLA 4的蛋白质深刻地影响对营养不良肌肉的免疫应答，损害。在这里提出的调查，我们将测试这一假设，确定机制，通过 CTLA 4-β介导的干预措施影响肌营养不良症，并评估长期使用CTLA 4-β介导的干预措施的安全性和有效性。在DMD的mdx小鼠模型中长期施用外源性CTLA 4。目的1.验证CTLA 4-Ig IG治疗可产生长时间免疫抑制的假设。在DMD小鼠模型中长期减少肌肉病理和改善功能。目的2.检验CTLA 4-β IG作用于淋巴细胞和骨髓细胞以减少肌肉损伤和减轻肌肉损伤的假设。炎症并促进营养不良肌肉中促再生环境。目的3.评估CTLA 4-Ig IG给药的安全性和对免疫细胞功能的长期影响。总之，这些发现可以使我们能够确定CTLA 4-Ig是否能抑制IG，一种安全有效的药物，其他人类疾病的治疗，可以为治疗DMD提供成功的新策略。