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

描述（由申请人提供）：我们基于GMCSF和IL15合成蛋白（GIFT15）生成了一类全新的免疫抑制剂。我们已经验证了其在小鼠中的使用，并进一步证明该化合物促进了诱导b调节细胞（又名iBregs）的发育，从而导致小鼠EAE的缓解。因此，本研究的资助将使我们更好地了解iBregs和GIFT15在EAE治疗中的作用机制。我们还将定义iBregs和重组GIFT15最安全和最有效的使用方法。此外，我们已经生成了GIFT15的人类版本，并证明了它对人类免疫细胞的抑制潜力。作为额外的步骤，小鼠细胞治疗方法的验证将使用从MS患者收集的人类免疫细胞，用人类GIFT15体外治疗。假设iBregs或GIFT15蛋白治疗在EAE小鼠中具有可接受的毒性特征，那么基于这项临床前工作，GIFT15人类同源物在I/II期临床研究中的转化使用可以迅速启动。事实上，将rGIFT15作为MS治疗的一部分，将为采用和验证该方法治疗多种疾病（如炎症性肠病（IBD）、移植物抗宿主病（GVHD）、类风湿性关节炎（RA）甚至细胞和器官移植）奠定基础。因此，GIFT15化合物作为一种在体外和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，用于医疗需求未得到满足的灾难性疾病，特别是ms。总之，这项研究将使我们能够追求iBregs和GIFT15蛋白药理产品的特性，并将为人类临床研究提供理性依据。

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.