B-lymphocyte Targeting Therapies for Autoimmune Diabetes

项目总结 而导致1型糖尿病(T1D)的胰岛细胞的自身免疫破坏最终是T细胞 在NOD小鼠模型和可能的人类中，很明显，B淋巴细胞扮演着一种 额外的关键致病作用。B淋巴细胞可能通过作为APC的最大亚群参与T1D的发病 有效地支持致病T细胞的激活。这是由于B淋巴细胞的存在，表达 免疫球蛋白(Ig)分子，可以有效地捕获并内化？细胞自身抗原。因此，存在缺陷的 通常阻断自身反应性B淋巴细胞和T淋巴细胞发育或活性的机制 为T1D做出贡献。由于它们在支持致病T细胞反应方面的作用，已经有相当多的 对开发可能的B淋巴细胞导向的T1D干预感兴趣。因此，这一点的中心假设是 建议增加对T1D的发育和功能活动基础的了解 NOD小鼠中相关的B淋巴细胞在确定它们可以被 有效地瞄准了。在这方面，目前数据表明，BAFF封锁可能是更有效的B- 淋巴细胞定向T1D干预优于抗CD20治疗。初步数据显示，这是一种 EphB2等位基因变异可能代表NOD小鼠的T1D易感性(IDD)基因，其作用在B- 淋巴细胞。转基因EphB2表达上调通过B淋巴细胞抑制T1D发育 从属过程。目标1将解决目前未知的问题，如果NOD B淋巴细胞升高 EphB2的表达失去了功能性激活糖尿病T细胞的能力，或者已经获得了 抑制致病效应物的功能我们之前也发现了一种基因和 抑制B淋巴细胞免疫球蛋白体细胞过程能力的药物途径 高突变(SHM)和类开关重组(CSR)抑制NOD小鼠T1D的发展。是这样的 B淋巴细胞不能进行SHM和CSR转化为调节性T细胞所致的T1D保护 表型(BREG)，通过增强免疫抑制活性来抑制致病T细胞 CD39/CD73胞外酶轴。最近的研究出人意料地表明，CD39基因的去除抑制了 在NOD小鼠中T1D的发育，这与相应的比例增加和减少有关 B淋巴细胞和T淋巴细胞总数。因此，目标2是确定消融CD39是否抑制NOD中T1D的发展 通过扩增B淋巴细胞，使其具有抑制致病T细胞反应的能力。我们还有 发现转基因表达Ig特异性B淋巴细胞的NOD小鼠T1D发病加速 识别存在于胰岛和神经元(NOD-PerIg小鼠)中的外周蛋白分子，但这 菌株还可能发展为与多发性硬化症(MS)相关的神经炎综合征。目标3将决定 B淋巴细胞驱动的T细胞群在介导T1D和神经炎发生中的潜在重叠 NOD-PerIg小鼠，并评估BAFF阻断是否能减轻这两种病理变化。

PROJECT SUMMARY While the autoimmune destruction of pancreatic ß-cells causing type 1 diabetes (T1D) is ultimately a T-cell mediated process, it is clear in the NOD mouse model and also likely humans, that B-lymphocytes play an additional key pathogenic role. B-lymphocytes likely contribute to T1D by being the subset of APC most efficiently supporting pathogenic T-cell activation. This is due to the presence of B-lymphocytes expressing immunoglobulin (Ig) molecules that can efficiently capture and internalize ß-cell autoantigens. Thus, defects in mechanisms normally blocking the development or activity of autoreactive B- as well as T-lymphocytes contribute to T1D. Due to their role in supporting pathogenic T-cell responses there has been considerable interest in developing possible B-lymphocyte directed T1D interventions. Hence, the central hypothesis of this proposal is that gaining an increased understanding of the developmental and functional activity basis of T1D relevant B-lymphocytes in NOD mice could be of significance in identifying a means by which they could be effectively targeted. In this regards, current data indicate BAFF blockade may be a more effective B- lymphocyte directed T1D intervention than anti-CD20 treatment. Preliminary data now indicate a hypomorphic Ephb2 allelic variant may represent a T1D susceptibility (Idd) gene in NOD mice acting at the level of B- lymphocytes. Transgenically elevating Ephb2 expression inhibits T1D development through a B-lymphocyte dependent process. Aim 1 will address the currently unknown question if NOD B-lymphocytes with elevated Ephb2 expression have lost an ability to functionally activate diabetogenic T-cells, or alternatively have gained a capacity to functionally suppress such pathogenic effectors. We also previously found that a genetic and pharmaceutical approach inhibiting the ability of B-lymphocytes to undergo the processes of Ig somatic hypermutation (SHM) and class switch recombination (CSR) inhibits T1D development in NOD mice. Such T1D protection resulted from B-lymphocytes unable to undergo SHM and CSR converting to a regulatory phenotype (Breg) that inhibit pathogenic T-cells through increased activity of the immunosuppressive CD39/CD73 ecto-enzyme axis. More recent studies unexpectedly indicate ablation of the CD39 gene inhibits T1D development in NOD mice, and this is associated with a respective proportional increase and decrease in total B- and T-lymphocytes. Thus, Aim 2 is to determine if ablation of CD39 inhibits T1D development in NOD mice by expanding B-lymphocytes with a capacity to suppress pathogenic T-cell responses. We have also found T1D onset is accelerated in NOD mice with B-lymphocytes transgenically expressing an Ig specificity recognizing the peripherin molecule present in both pancreatic islets and neurons (NOD-PerIg mice), but this strain can also develop a potential multiple sclerosis (MS) relevant neurtitis syndrome. Aim 3 will determine the potential overlap in B-lymphocyte driven T-cell populations mediating T1D and neuritis development in NOD-PerIg mice, and assess if either of these pathologies can be attenuated by BAFF blockade.