Therapeutic potential of PSG1 administration in GVHD

 描述(申请人提供)：异基因干细胞骨髓移植可用于治疗某些恶性肿瘤、遗传免疫缺陷、血红蛋白疾病和自身免疫性疾病。由于其潜在的严重并发症，尤其是移植物抗宿主病(GvHD)，该疗法的广泛应用尚未实现。因此，迫切需要有效且副作用少的预防和治疗急性移植物抗宿主病(AGvHD)的创新疗法，尤其是对激素难治性患者。生理学 妊娠等过程为显著降低aGvHD死亡率的新干预措施提供了线索。与过去的看法相反，过去几年收集的数据表明，怀孕并不是一种免疫抑制状态，而是在怀孕期间，母胎界面和全身的免疫反应发生了质的变化。这些变化是必须的，以耐受半异基因胎儿，同时保护母亲免受感染。胎盘滋养层细胞分泌的可溶性因子有助于孕期耐受性免疫环境的建立。PSG1就是这样一个因子，是人类怀孕期间母血中含量最丰富的滋养层蛋白。我们已经证明PSG1是为数不多的已知的免疫调节细胞因子转化生长因子-β(转化生长因子-β)的激活剂之一，转化生长因子β是由细胞以潜伏/不活跃的形式分泌的。转化生长因子-β调节先天免疫系统和获得性免疫系统细胞的表型和功能，并下调这些细胞的促炎细胞因子的表达。此外，转化生长因子-β是诱导和维持调节性T细胞(Treg)所必需的。在两个活体小鼠模型中，我们发现PSG1介导的活性转化生长因子-β1的增加导致Tregs的绝对数量和百分比增加。Tregs在aGvHD中有良好的有益效果，但它们的增加并不能阻止供者淋巴细胞的移植物抗白血病效应。因此，增加Tregs的数量以降低与aGVHD相关的死亡率被认为是目前所有需要骨髓移植的病理学的一种新的和有效的策略。然而，Treg的体外扩增方案昂贵且耗时，限制了其临床应用。为了避免这些问题，增加体内Treg细胞的数量提供了一个有价值的替代方案。因此，我们认为PSG1具有以前未被探索的治疗潜力，因为它的免疫调节功能，以及在正常妊娠期间发现的这种蛋白的高血清浓度，它没有毒性或副作用。为了验证我们的假设，我们将在临床前模型中应用重组PSG1或对照蛋白来实现以下目标：1)评估PSG1在预防急性移植物抗宿主病方面的潜在治疗效果并确定其作用机制；2)确定在异基因造血骨髓移植后应用PSG1是否保留了供体细胞的移植物抗肿瘤活性。

 DESCRIPTION (provided by applicant): Allogeneic stem cell bone marrow transplantation can be used to cure some malignancies, genetic immunodeficiencies, hemoglobinopathies, and autoimmune disease. Widespread application of this therapy is not yet realized because of its potential serious complications, most notably graft- versus-host disease (GvHD). Therefore, innovative therapies to both prevent and treat acute GvHD (aGvHD) that are effective and have fewer side effects, particularly for steroid refractory patients are urgently needed. Physiological processes such as pregnancy provide a clue to novel interventions to significantly reduce aGvHD mortality. Contrary to old perceptions, data gathered over the last years has shown that pregnancy is not a state of immunosuppression, rather during pregnancy there are qualitative changes in the immune response at the maternal-fetal interface and systemically. These changes are required to tolerate the semi-allogeneic fetus while protecting the mother from infections. Soluble factors secreted by trophoblast cells of the placenta contribute to the establishment of the tolerogenic immune environment during pregnancy. PSG1 is such a factor and is the most abundant trophoblastic protein in maternal blood during human pregnancy. We have shown that PSG1 is among the few known activators of the immune-regulatory cytokine transforming growth factor beta (TGF-β), which is secreted from cells in a latent/inactive form. TGF-β regulates the phenotype and function of cells of the innate and adaptive immune systems and down regulates the expression of pro-inflammatory cytokines by these cells. In addition, TGF-β is required for the induction and maintenance of regulatory CD4+ Foxp3+ T cells (Tregs). In two in vivo mouse models, we showed that PSG1-mediated increase in active TGF-β1 results in an increase in the absolute number and percentage of Tregs. Tregs have a well demonstrated beneficial effect in the context of aGvHD while their increase does not prevent the graft-versus-leukemia effect of donor lymphocytes. Therefore increasing the number of Tregs to decrease mortality associated with aGVHD is considered a novel and valid strategy for all current pathologies requiring bone marrow transplantation. However, protocols for in vitro Treg expansion are costly and time-consuming limiting their clinical use. To circumvent these problems, increasing the Treg cell numbers in vivo provides a valuable alternative. Therefore, we propose that PSG1 administration has a previously unexplored therapeutic potential due to its immune-regulatory function and its lack of toxicity or side effects, supported by the high serum concentration of this protein found during normal pregnancy. To test our hypothesis, we will administer recombinant PSG1 or a control protein in a pre-clinical model to achieve the following aims: 1) Evaluate the potential therapeutic effects of treatment with PSG1 in preventing acute graft-versus-host disease and define its mechanism of action and 2) Determine whether administration of PSG1 preserves the graft-versus-tumor activity of donor cells following allogeneic hematopoietic bone marrow transplantation.