Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
复制标题
DOI：
10.1172/jci32405
复制
发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Wen, Li
中科院分区：
文献类型：
--
作者：
Hu, Chang-Yun;Rodriguez-Pinto, Daniel;Wen, Li
B细胞在促进1型糖尿病发病机制中的确切作用仍不明确。在这里，我们证明小鼠的B细胞耗竭可以预防或延迟糖尿病，在明显的高血糖后逆转糖尿病，并导致抑制疾病的细胞的发展。为了确定治疗性B细胞耗竭的功效和潜在机制，我们产生了在B细胞上表达人CD 20（hCD 20）的转基因NOD小鼠。用hCD 20特异性抗体的单周期治疗暂时耗尽了B细胞，并显著延迟和/或减少了糖尿病的发作。此外，超过三分之一的糖尿病小鼠的临床高血糖症可以逆转。尽管对抗体、细胞因子和抗原呈递给T细胞的影响被认为是重要的，但B细胞耗竭对各种自身免疫性疾病具有治疗作用的原因尚不清楚。在B细胞耗竭的NOD小鼠中，我们确定了我们认为是一种新的机制，通过这种机制，B细胞耗竭可能会导致THP和调节性B细胞的扩增而长期缓解。我们的研究结果表明，即使在已建立的疾病的临床疗效，并确定治疗作用的机制，将指导设计和评价患者的平行研究。
The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.