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（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、遗传性免疫缺陷、血红蛋白病和自身免疫性疾病。由于其潜在的严重并发症，最显著的是移植物抗宿主病（GvHD），这种疗法的广泛应用尚未实现。因此，迫切需要有效且副作用较少的预防和治疗急性GvHD（aGvHD）的创新疗法，特别是对于类固醇难治性患者。生理 妊娠等过程为显著降低aGvHD死亡率的新干预提供了线索。与旧的观念相反，过去几年收集的数据表明，怀孕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。这些变化是耐受半同种异体胎儿，同时保护母亲免受感染所必需的。由胎盘滋养层细胞分泌的可溶性因子有助于妊娠期间致耐受性免疫环境的建立。PSG 1就是这样一种因子，是人类妊娠期间母体血液中最丰富的滋养层蛋白。我们已经证明，PSG 1是免疫调节细胞因子转化生长因子β（TGF-β）的少数已知激活剂之一，TGF-β以潜伏/非活性形式从细胞分泌。TGF-β调节先天性和适应性免疫系统的细胞的表型和功能，并下调这些细胞的促炎细胞因子的表达。此外，TGF-β是诱导和维持调节性CD 4 + Foxp 3 + T细胞（TCFs）所必需的。在两个体内小鼠模型中，我们发现PSG 1介导的活性TGF-β1的增加导致TGFs的绝对数量和百分比增加。在aGvHD的背景下，TdR具有充分证明的有益作用，而它们的增加并不阻止供体淋巴细胞的移植物抗白血病作用。因此，增加THBG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新的和有效的策略。然而，用于体外Treg扩增的方案是昂贵且耗时的，限制了它们的临床应用。为了避免这些问题，增加体内Treg细胞数量提供了一种有价值的替代方案。因此，我们建议，PSG 1管理具有以前未开发的治疗潜力，由于其免疫调节功能和其缺乏毒性或副作用，由正常妊娠期间发现的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给予重组PSG 1或对照蛋白，以实现以下目标：1）评价PSG 1治疗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PSG 1给药是否保留了移植物抗宿主病，异基因造血骨髓移植后供体细胞的肿瘤活性。