Following acute radiation exposure, in addition to traumatic injuries such as fractures, lacerations, and burns, radiation syndromes involving the central nervous, gastrointestinal, cutaneous, and hematopoietic systems can ensue. Of the these syndromes, treatment has been identified for the hematopoietic syndrome (exposure of 0.7-10 Gy), in which the attendant morbidities of anemia, thrombbcytopenia, and the infectious complications associated with neutropenia, can be treated with both colony-stimulating factors, aggressive use of anti-microbials, and stem cell transplantation. The strategy involving allogeneic stem cell transplantation, due to the morbidity and mortality associated with graft versus host disease (GVHD) and graft failure, could be beneficial for individuals exposed to 4-10 Gy by hastening immunologic and hematologic reconstitution, however due to the risks of treatment, this application has been limited. Recently co-transplantation of the intact bone marrow microenvironment as bone fragments along with allogeneic stem cells has led to rapid engraftment and reduction in GVHD. Since mesenchymal stem cells (MSC) can be induced to differentiate into the in vivo components of the bone marrow microenvironment, it is likely that these cells could function similarly to the transplanted bone fragments. In murine experiments, we have observed MSC to rescue lethally irradiated hosts that had received sub-optimal numbers of stem cells, permit the reduction of host conditioning while establishing equal or better levels of engraftment than the combination of intensive host conditioning and untreated HSC grafts, enable stable xenogeneic enraftment (rat?> mouse) and reduce GVHD seven fold. In this proposal, we will test three main feasibility issues for the widespread use of an MSC product following a radiation incident: timing and physiological effectiveness of the engineered stem cell graft, prevention of GVHD, and the use of unrelated ex vivo expanded cryopreserved MSC in a pre-clinical primate model. First, in a lethal irradiation model, we will test whether MSC engineered hematopoietic grafts can be administered in a delayed fashion with similar efficacy, to those administered on day 0. In sub-lethally irradiated mice, we will test whether MSC alone without hematopoietic stem cells can hasten hematopoietic recovery and thereby improve immune reconstitution. To test the effect of MSC on immune function recovery, recipients will be challenged with a Klebsiella inoculum. Second, we will test whether suppression of GVHD is due to the generation of regulatory cells or the direct effect of MSC on donor T cells. Last, using the preclinical cynomolgus monkey model of allogeneic stem cell transplantation, we will test whether exposure to 600cGy of irradiation can be successfully treated with MSC-engineered stem cell grafts. To simulate conditions that might mimic MSC availability clinically, we will test whether the use of either donor or 3rd party cryopreserved MSC can aid allogeneic hematopoietic engraftment, since our murine data indicate that the effect of MSC on engraftment can occur with an MSC source unrelated to the donor. The use of 3rd party ex vivo expanded cryopreserved MSC is clinically attractive, since it potentially reduces the time to obtain MSC while increasing widespread availability for clinical use.
| Polchert, David; Sobinsky, Justin; Douglas, Gw et al. (2008) IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 38:1745-55 |
