Attenuation of Radiation-Induced GI Injury by Cultured Myeloid Progenitors

描述（由申请人提供）：我们的长期目标是开发一种含有人髓系祖细胞的通用的基于细胞的疗法，以减轻辐射诱导的胃肠道或造血损伤。放射（XRT）仍然是治疗恶性肿瘤的重要治疗方式。胃肠道（GI）和造血系统的损伤是辐射照射的严重后遗症，很少有有效的照射后治疗。直接细胞破坏、趋化因子/细胞因子产生的上调、先天免疫和凝血受损情况下的微生物侵入均导致XRT诱导的胃肠道（GI）损伤。我们推测，髓系/巨核细胞祖细胞池的补充将通过造血前体的替代和胃肠道粘膜的免疫调节来保护免受XRT诱导的损伤。这些祖细胞是充分表征的、短寿命的亚群，统称为髓样祖细胞，其产生粒细胞、巨噬细胞、树突细胞、红细胞和血小板。我们已经完善了离体培养条件，导致这些骨髓祖细胞（MPc）的成功扩增和冷冻保存。我们的假设的基本原理已经通过我们的清髓性辐射损伤的临床前模型建立，在该模型中，我们已经证明了单次输注同种异体MPc可以防止随后的致命剂量的烟曲霉菌或铜绿假单胞菌的攻击。此外，我们还在初步研究中证明了胃肠道组织学变化的衰减和对高剂量照射后死亡的保护。放射治疗作为恶性肿瘤的治疗或作为造血细胞移植的准备方案的医学应用通常伴随着胃肠道（GI）损伤的严重后果。我们的意外发现，同种异体，培养衍生的骨髓祖细胞保护免受辐射诱导的胃肠道损伤将有一个显着的积极影响，这一群体的生存和生活质量。安全有效的“现成”治疗的可用性也将对地方和联邦政府应对核电站事故、恐怖爆炸或其他局部放射性灾难造成的大规模伤亡的能力产生重大积极影响。

DESCRIPTION (provided by applicant): Our long term goal is to develop a universal cell-based therapy containing human myeloid progenitor cells to attenuate radiation-induced gastrointestinal or hematopoietic injury. Radiation (XRT) remains an important therapeutic modality in the treatment of malignancies. Injury to the gastrointestinal tract (GI) and hematopoietic system are serious sequelae of radiation exposure for which there are few effective post-exposure therapies. Direct cellular disruption, upregulation of chemokine/cytokine production, microbial invasion in the setting of impaired innate immunity and coagulation all contribute to XRT-induced gastrointestinal (GI) injury. We postulate that the repletion of the myeloid/megakaryocyte progenitor pools will protect against XRT-induced injury by the replacement of hematopoietic precursors and immunomodulation of the gastrointestinal mucosa. These progenitors are well- characterized, short-lived, subpopulations collectively referred to as myeloid progenitors that give rise to granulocytes, macrophages, dendritic cells, erythrocytes and platelets. We have refined ex-vivo culture conditions resulting in the successful expansion and cryopreservation of these myeloid progenitor cells (MPc). The rationale for our hypothesis has been established by our preclinical models of myeloablative radiation injury in which we have demonstrated that a single infusion of allogeneic MPc protects against a subsequent challenge with an otherwise lethal dose of Aspergillus fumigatus or pseudomonas aeruginosa. Furthermore, we have also demonstrated in preliminary studies attenuation of histologic changes in the gastrointestinal tract and protection against death following higher doses of irradiation. Medical application of radiation as a therapy for malignancies or as a preparative regimen for hematopoietic cell transplantation is often accompanied by the severe consequence of gastrointestinal (GI) injury. Our unexpected finding that allogeneic, culture-derived myeloid progenitor cells protect against radiation-induced GI injury will have a significant positive impact on the survival and quality of life of this population. The availability of a safe and effective, "off-the-shelf" treatment will also have a significant positive impact on the ability of local and federal governments to respond to mass casualties as a result of a nuclear power plant accident, terrorist detonation, or other localized radiological disasters.