Inducible B-regulatory cells (iBREGs) for treatment of Multiple Sclerosis

描述(由申请人提供)：我们已经基于GMCSF和IL15合成蛋白产生了一种全新的免疫抑制剂，我们称之为GIFT15。我们已经在小鼠身上验证了它的使用，并进一步证明了这种化合物促进了可诱导的B调节细胞(又名iBregs)的发展，从而导致小鼠EAE的缓解。因此，这项研究的资助将使我们能够更好地了解iBregs和GIFT15在治疗EAE中的作用机制。我们还将定义iBregs和重组GIFT15的最安全和最有效的使用。此外，我们还产生了人类版本的GIFT15，并展示了它对人类免疫细胞的抑制潜力。作为额外的步骤，将使用从多发性硬化症患者收集的人类免疫细胞来验证小鼠细胞治疗方法，这些细胞在体外用人类GIFT15治疗。假设iBregs或GIFT15蛋白疗法在EAE小鼠身上产生了临床益处，并具有可接受的毒性特征，那么在这项临床前工作的基础上，可以迅速启动在I/II期临床研究中使用人类GIFT15的同源基因。事实上，在多发性硬化症的治疗中使用rGIFT15作为治疗的一部分，将作为采用和验证这一方法的基础，用于各种疾病，如炎症性肠病(IBD)、移植物抗宿主病(GVHD)、类风湿性关节炎(RA)，甚至在细胞和器官移植的背景下。因此，GIFT15化合物作为一种在体外和可能在体内产生抑制细胞的方法代表了一种广泛的临床应用方法，用于治疗未得到满足的医疗需求的灾难性疾病，尤其是MS。总之，这项研究将使我们能够继续研究iBregs和GIFT15蛋白药理产品的特征，并将作为人类临床研究的理性。

DESCRIPTION (provided by applicant): We have generated a completely new class of immune suppressive agents based on a GMCSF and IL15 synthetic protein we called GIFT15. We've validated its use in mice and have further demonstrated that this compound promotes development of inducible B-regulatory cells (aka as iBregs) which leads to remission of EAE in mice. Therefore, the funding of this study will enable us to better understand the mechanism of action of iBregs and GIFT15 in the treatment of EAE. We will also define the safest and most efficient use of iBregs and recombinant GIFT15. In addition, we have generated the human version of GIFT15 and demonstrated its suppressive potential on human immune cells. As an additional step, validation of the mouse cell therapy approach will be achieved using human immune cells collected from MS patients, ex vivo treated with the human GIFT15. Assuming that iBregs or GIFT15 protein therapy leads to clinical benefit with an acceptable toxicity profile in EAE mice, the translational use of the human ortholog of GIFT15 in phase I/II clinical studies could be rapidly initiated based on this pre-clinical work. Indeed, the use of rGIFT15 in the context of MS as part of a therapeutic treatment will serve as the basis for the adoption and validation of this approach for a variety of diseases such as inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), rheumatoid arthritis (RA) or even in the context of cell and organ transplantations. Thus, the utility of the GIFT15 compound as a way to generate suppressive cells in vitro and likely in vivo represents an approach with a wide array of clinical applications for catastrophic illnesses with unmet medical needs, especially MS. In sum, this study will enable us to pursue the characterization of iBregs and GIFT15 protein pharmacological product and will serve as rational for human clinical studies.