A Nonhuman Primate Model of the Hematopoietic Acute Radiation Syndrome Plus Medical Management

Abstract

The development of medical countermeasures against the hematopoietic sub-syndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to the morbidity and mortality. Herein, we define these parameters for the nonhuman primate exposed to total-body radiation and administered medical management. A blinded, randomized study (n=48 rhesus macaques) determined the lethal dose response relationship using bilateral, 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90Gy at 0.80Gy minute−1. Following irradiation animals were monitored for complete blood counts, body weight, temperature, diarrhea, and hydration status for 60 days. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics and nutrition. The primary endpoint was survival at 60 days post irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents and tissue histology. The study defined an LD30/60 of 7.06Gy, LD50/60 of 7.52Gy, and an LD70/60 of 7.99Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

“…Dashed lines represent that 95% confidence interval and points reflect the actual experimental data. The cohorts were provided supportive medical care as described by Farese et al (2012a). TBI was conducted using 6 MV LINAC-derived photons at a dose rate of approximately 0.8 Gy min −1 .…”

“…The dose response relationship (DRR) for HARS in the rhesus macaque under a regimen of medical management has been well described by Farese et al (2012a andb, 2013). Intralaboratory adherence to standard operating procedures (SOPs) reduces study-to-study variability and adds credence to subsequent changes in the DRR when evaluating potential new MCM.…”

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

“…The hematopoietic system is highly sensitive to IR, and in particular, IR doses beyond 2 Gy can lead to myelosuppression that is characterized by neutropenia, lymphocytopenia, and thrombocytopenia. Collectively, hematopoietic acute radiation syndrome (H-ARS) increases the risk of infection, bleeding, and death (1)(2)(3)(4)(5)(6)(7)(8)(9). There is an unmet need for effective interventions to mitigate the progression of H-ARS after IR exposure (10).…”

The MCART Consortium Animal Model Series

“…The trigger-based administration of medical management can be "population-based," as for mouse studies, or "patient-based" for studies using NHP. There is a significant preclinical database supporting the use and timing of effective medical management in mice, canines, and NHP (MacVittie et al 1991(MacVittie et al , 2001Sorensen et al 1960;Booth et al 2012b;Farese et al 2012a;Plett et al 2012;Garofalo et al 2014;MacVittie 2012MacVittie , 2014. All supportive care measures are adapted from consensus-based clinical standards of treatment (Waselenko et al 2004;Schimpff 1990;Hughes 2002;Gafter-Gvili et al 2005;Freifeld et al 2011;Fliedner et al 2001).…”