Therapeutic potential of PSG1 administration in GVHD

PSG1 给药在 GVHD 中的治疗潜力

• 批准号: 9111289
• 负责人: Gabriela S Dveksler
• 金额: $ 19.25万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-18 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111289
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Adverse effects; Affinity; Allogenic; Allografting; Antigens; Arthritis; Autoimmune Diseases; Binding; Biological; Blood; Blood Circulation; Bone Marrow Stem Cell Transplantation; Bone Marrow Transplantation; Cell Count; Cell physiology; Cells; Clinical; Clinical Trials; Colitis; Collagen-Induced Arthritis; Complex; Cytoprotection; Data; Development; Disease; Environment; Fetus; Genetic; Glycoproteins; Goals; Graft Rejection; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunosuppression; In Vitro; Infection; Infectious Agent; Inflammatory; Inflammatory Bowel Diseases; Innovative Therapy; Insulin-Dependent Diabetes Mellitus; Intervention; Intestines; Knowledge; Lymphocyte; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Maternal-Fetal Exchange; Mediating; Minor; Modeling; Molecular; Morbidity - disease rate; Mothers; Organ; Organ Transplantation; Pathology; Patients; Peptides; Perception; Phase; Phenotype; Physiological Processes; Placenta; Play; Pre-Clinical Model; Pregnancy; Protein Family; Proteins; Protocols documentation; Recombinants; Refractory; Regulatory T-Lymphocyte; Risk; Role; Serum; Severities; Steroids; Syndrome; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Transplantation; Toxic effect; Transforming Growth Factor beta; Translating; allograft rejection; base; cytokine; effective therapy; fetal; graft vs host disease; in vivo; innovation; leukemia; microbial; mortality; mouse model; neoplastic cell; novel; novel therapeutics; polypeptide; prevent; protective effect; public health relevance; receptor; treatment strategy; trophoblast

 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.

 描述（由应用提供）：Allonece干细胞骨髓移植可用于治愈某些恶性肿瘤，遗传免疫缺陷，血红蛋白病和自身免疫性疾病。由于其潜在的严重并发症，最著名的是治疗疾病（GVHD），因此尚未实现这种疗法的宽度应用。因此，有效且副作用较少的创新疗法可以预防和治疗急性GVHD（AGVHD），尤其是对于立体难治性患者而言，紧急需要。生理 怀孕等过程为新的干预措施提供了线索，以显着降低AGVHD死亡率。与旧的看法相反，过去几年收集的数据表明，怀孕不是免疫抑制的状态，而是在怀孕期间，在母亲 - 狂热界面和系统地，免疫反应发生了质量变化。需要这些变化来耐受半合成性胎儿，同时保护母亲免受感染的侵害。胎盘滋养细胞分泌的可溶性因子有助于在怀孕期间建立耐受性免疫环境。 PSG1是一个因素，是人类怀孕期间物物血液中最丰富的滋养细胞蛋白。我们已经证明，PSG1是免疫调节细胞因子转化生长因子β（TGF-β）的少数已知活化剂之一，该因子转化生长因子β（TGF-β），该因子以潜在/非活动形式从细胞中分泌。 TGF-β调节先天和适应性免疫系统细胞的表型和功能，并下降这些细胞通过这些细胞调节促炎性细胞因子的表达。此外，TGF-β是诱导和维持调节性CD4+ FOXP3+ T细胞（Tregs）所必需的。在两个体内小鼠模型中，我们表明PSG1介导的活性TGF-β1的增加导致Tregs的绝对数量和百分比增加。 Treg在AGVHD的背景下具有很好的有益作用，而它们的增加并不能阻止供体淋巴细胞的移植物 - 抗脉络膜作用。因此，增加了与AGVHD相关的死亡率的Treg数量被认为是所有需要骨髓移植的当前病理的新颖和有效策略。但是，体外Treg扩张的方案是昂贵的，并且耗时限制了它们的临床使用。为了解决这些问题，在体内增加Treg细胞数量提供了一个有价值的选择。因此，我们建议PSG1给药具有以前出乎意料的治疗潜力，这是由于其免疫调节功能及其缺乏毒性或副作用，并由正常怀孕期间这种蛋白质的高血清浓度支持。为了检验我们的假设，我们将在临床前模型中管理重组PSG1或对照蛋白，以实现以下目的：1）评估PSG1治疗在防止急性移植抗菌疾病中的潜在治疗作用移植。