Antibody-mediated suppression of autoimmunity in humanized mice

摘要 我们最近报道，促炎细胞因子激素瘦素加速了发展， 在狼疮易感（NZB x NZW）F1（NZB/W）小鼠中系统性红斑狼疮（SLE）的进展。 有趣的是，在严重肾炎的NZB/W小鼠中，瘦素抑制与瘦素水平的显著增加相关。 生存和改善多种疾病的表现，这表明这种方法可以代表一种 这是一种新的治疗干预方式。基于这些发现，我们的目标是测试 以瘦素为基础的干预治疗人类SLE以减少循环自身抗体的可能性，延迟 疾病进展和改善的结果。具体来说，我们开发了完全人源性的抗瘦素抗体和抗 瘦素受体单克隆抗体（mAb）将在两种不同的小鼠模型系统中进行测试 通过以下具体目的用人细胞重建：1）评估体内治疗性 在人源化狼疮小鼠中使用人mAb的瘦素抑制在SLE中的功效; 2）研究 通过瘦素阻断在体内诱导的机制。总之，这些研究将告知瘦素的功效 在人类SLE中的拮抗作用，为疾病的后续临床试验奠定了关键基础。

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.