Antibody-mediated suppression of autoimmunity in humanized mice

抗体介导的人源化小鼠自身免疫抑制

• 批准号: 9895546
• 负责人: ANTONIO LA CAVA
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-17 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895546
• 关键词: Abbreviations; Address; Aftercare; Antibodies; Antigen-Antibody Complex; Antinuclear Antibodies; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bioavailable; Biological; Biological Models; Biological Products; CD34 gene; Cells; Cellular Metabolic Process; Clinical; Clinical Trials; Data; Dendritic Cells; Deposition; Development; Disease; Disease Management; Disease Progression; Engraftment; Evaluation; Flare; Goals; Hematopoietic stem cells; Histopathology; Hormones; Human; Immune; Immune response; Immunodeficient Mouse; Injections; Interferon Type I; Intervention; Investigation; Kidney; Kidney Diseases; Leptin; Lupus; Measurement; Mediating; Medical; Modality; Modeling; Monoclonal Antibodies; Mus; New Agents; Organ; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Placebos; Population; Pristane; Production; Publishing; Reporting; Reproduction; Risk; Role; Series; Severity of illness; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; Work; autoreactivity; base; belimumab; comparison group; cytokine; effectiveness validation; human monoclonal antibodies; humanized mouse; immunogenicity; improved; improved outcome; in vivo; inhibitor/antagonist; leptin receptor; lupus-like; monocyte; mouse model; novel therapeutic intervention; novel therapeutics; outcome forecast; receptor; reconstitution; response; seropositive; side effect; transcriptome sequencing

Abstract We recently reported that the proinflammatory cytokine hormone leptin accelerated the development and progression of systemic lupus erythematosus (SLE) in lupus-prone (NZB x NZW)F1 (NZB/W) mice. Interestingly, leptin inhibition in severely nephritic NZB/W mice associated with a significant increase in survival and amelioration of multiple disease manifestations, suggesting that this approach could represent a new modality of therapeutic intervention in the disease. Building on these findings, we aim to test the possibility of leptin-based intervention in human SLE for the reduction of circulating autoantibodies, delayed disease progression, and improved outcomes. Specifically, we developed fully human anti-leptin and anti- leptin receptor monoclonal antibodies (mAb) that will be tested in two different mouse model systems reconstituted with human cells through the following specific aims: 1) To evaluate the in vivo therapeutic efficacy of leptin inhibition in SLE using human mAb in humanized lupus mice; 2) To investigate the mechanisms induced in vivo by leptin blockade. Together, these studies will inform about the efficacy of leptin antagonism in human SLE, laying critical grounds for subsequent clinical trials in the disease.

摘要 我们最近报道，促炎症细胞因子激素瘦素促进了细胞的发育和 狼疮易感(NZB X NZW)F1(NZB/W)小鼠系统性红斑狼疮的进展。 有趣的是，严重肾炎NZB/W小鼠的瘦素抑制与显著增加的 多种疾病表现的存活和改善，表明这种方法可能代表着 治疗干预该病的新模式。在这些发现的基础上，我们的目标是测试 人类系统性红斑狼疮基于瘦素的干预降低循环自身抗体的可能性 疾病的进展和改善的结果。具体地说，我们开发了完全人类抗瘦素和抗- 瘦素受体单抗将在两种不同的小鼠模型系统中进行测试 通过以下特定目的重组人细胞：1)评价体内治疗 人源化狼疮小鼠应用人源单抗抑制瘦素治疗SLE的疗效 瘦素阻断的体内诱导机制。总之，这些研究将为瘦素的疗效提供信息。 在人类系统性红斑狼疮中的拮抗作用，为随后的疾病临床试验奠定了关键基础。