Stem cell rescue for radiation accident victims

辐射事故受害者的干细胞救援

• 批准号: 7676115
• 负责人: Christian S Kuhr
• 金额: $ 71.71万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7676115
• 关键词: AMD3100; Allogenic; Allografting; Autologous; Blood; Bone Marrow; CD44 gene; CXCR4 Receptors; Calcineurin inhibitor; Canis familiaris; Cell Death; Cell Transplantation; Cells; Development; Dose; Dose-Rate; Engraftment; Ensure; FCGR3B gene; FK506; FK778; Failure; Granulocyte Colony-Stimulating Factor; HLA Antigens; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Histocompatibility; Hour; Human; Immunity; Immunosuppression; Immunosuppressive Agents; Injection of therapeutic agent; Injury; Intervention; KLRD1 gene; Marrow; Methods; Methotrexate; Modeling; Monoclonal Antibodies; Natural Killer Cells; New Agents; Numbers; Outcome; Parents; Peripheral Blood Mononuclear Cell; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Prevention; Process; Public Health; Purines; Radiation; Radiation Accidents; Radiation Injuries; Range; Rate; Recovery; Registries; Reporting; Role; Siblings; Sirolimus; Source; Stem cells; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Transfusion; Treatment Protocols; Vorinostat; Whole-Body Irradiation; Work; base; chemokine; day; disorder prevention; graft vs host disease; killer T cell; mycophenolate mofetil; novel; peripheral blood; pre-clinical; preclinical study; predictive modeling; prevent; purine; small molecule

Radiation poses a significant threat to public health from either accidental or deliberate exposures, proving lethal at higher doses due primarily to the effects on hematopoiesis. When irreversible injury to the bone marrow occurs hematopoietic cell transplantation is required for survival, and realistically after unplanned high-level exposure, this would be carried out within 2 to 4 days following injury, precluding attempts at identifying human leukocyte antigen (HLA) matched unrelated donors from existing registries. Therefore the most relevant sources of stem cells in such a setting would be offspring or parents of the victim who would either be HLA matched or, more likely, be HLA mismatched. We have previously reported preclinical studies in a canine model demonstrating that HCT from major histocompatibility (MHC) matched littermates was lifesaving after radiation exposure. The proposed studies will use the preclinical canine model to expand on this work and to develop therapy to rescue victims of unplanned radiation exposure by testing the hypothesis that HCT can be achieved across MHC barriers from HLA haploidentical donors. The significance of these studies is underpinned by the failure of previous attempts at HCT after radiation accidents and they will be based on already existing MHC mismatched HCT strategies by including rapid donor stem cell mobilization and the use of novel pharmacological immunosuppression to facilitate engraftment and control graft versus host disease. The first specific aim will define the barrier to HCT engraftment imparted by varying doses of myeloablative total body irradiation (TBI) and delayed administration of hematopoietic stem cells. The second aim expands upon these findings by evaluating additional maneuvers to overcome the host versus graft barrier consisting both of innate (NK cells) and adaptive (T cells) immunities. The third aim develops regimens to both control GVHD and enhance donor HCT engraftment. At the conclusion of these studies we anticipate having developed methods that allow for consistent engraftment of MHC-haploidentical cells after accidental total body irradiation exposure of marrow-lethal intensity without significant GVHD. The development of such methods will ensure that large numbers of people could receive concise and definitive therapeutic regimens to treat lethal radiation injury.

辐射对公众健康构成重大威胁，无论是意外暴露还是故意暴露，在较高剂量下被证明是致命的，主要是由于对造血的影响。当骨髓发生不可逆转的损伤时，需要造血细胞移植才能存活，实际上，在意外的高水平暴露后，这将在损伤后2-4天内进行，排除了从现有登记中识别人类白细胞抗原(HL A)匹配的无关供者的尝试。因此，在这种情况下，最相关的干细胞来源将是受害者的后代或父母，他们要么是匹配的，要么更有可能是不匹配的。我们之前曾报道过临床前研究 在一种犬模型中，主要组织相容性(MHC)匹配的同种胎的HCT在辐射暴露后是拯救生命的。拟议中的研究将使用临床前犬模型来扩展这项工作，并通过测试以下假设来开发抢救计划外辐射受害者的治疗方法：HCT可以跨越HLA半相合捐赠者的MHC屏障。这些研究的意义是基于先前在辐射事故后对HCT的尝试失败，它们将基于现有的MHC不匹配的HCT策略，包括快速动员供者干细胞和使用新的药理免疫抑制以促进植入和控制移植物抗宿主病。 寄主疾病。第一个具体目标将确定不同剂量的清髓性全身照射(TBI)和延迟给药造血干细胞所产生的HCT植入障碍。第二个目的是通过评估克服宿主对移植物的天然(NK细胞)和获得性(T细胞)免疫的屏障的额外操作来扩展这些发现。第三个目标是开发既能控制移植物抗宿主病又能促进供者血细胞移植的治疗方案。在这些研究的结论中，我们预计已经开发出允许MHC-单倍体相合细胞在 意外全身照射暴露的骨髓致死强度无明显移植物抗宿主病。这种方法的发展将确保大量的人能够得到简明和明确的治疗方案来治疗致命的辐射损伤。