Attenuation of Radiation-Induced GI Injury by Cultured Myeloid Progenitors

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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.