The MCART Consortium Animal Models Series

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The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures.

Section: Introductionmentioning

confidence: 99%

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

Thrall

Love

OʼDonnell³

et al. 2015

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“…The foundation by which MCART has established a pipeline for investigating MCMs is development of well-characterized radiation animal models that accurately mimic the key organ-specific sequelae observed in humans and involving hematopoietic-ARS (H-ARS), acute and prolonged gastrointestinal-ARS (GI-ARS), and delayed lung injury (lung-DEARE). Furthermore, the MCART models have been progressively refined to encompass an understanding of the dose- and time-dependent organ-specific and multi-organ injury, morbidity, and mortality in a consensus paradigm (MacVittie 2014). That is, the MCART animal models are designed to evaluate latency, incidence, severity, and duration of organ-specific injuries and how these injuries are linked to potential multi-organ injuries and outcome.…”

Section: Introductionmentioning

confidence: 99%

Citrulline as a Biomarker in the Non-human Primate Total- and Partial-body Irradiation Models

Jones¹,

Bennett²,

Carter³

et al. 2015

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The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- and partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min−1) in nonhuman primate models was investigated. The irradiation exposure covered gastrointestinal injuries spanning lethal, mid-lethal, and sub-lethal doses. The acute gastrointestinal injury was assessed via measurement of plasma citrulline and small intestinal histopathology over the first 15 days following radiation exposure and included total-body irradiation at 13.0 Gy, 10.5 Gy, and 7.5 Gy and partial-body irradiation at 11.0 Gy with 5% bone marrow sparing. The dosing schemes of 7.5 Gy total-body irradiation and 11.0 Gy partial-body irradiation included time points out to day 60 and day 180, respectively, which allowed for correlation of plasma citrulline to prolonged gastrointestinal injury and survival. Plasma citrulline values were radiation-dependent for all radiation doses under consideration with nadir values ranging from 63–80 % lower than radiation-naïve NHP plasma. The nadir values were observed at day 5 to 7 post irradiation. Longitudinal plasma citrulline profiles demonstrated prolonged gastrointestinal injury resulting from acute high-dose irradiation had long lasting effects on enterocyte function. Moreover, plasma citrulline did not discriminate between total-body or partial-body irradiation over the first 15 days following irradiation and was not predictive of survival based on the radiation models considered herein.

“…The exposure protocols using the WTLI and PBI/BM2.5 had respective mortalities of 70% and 65% consequent to radiation-induced lung injury over the 180d study duration (MacVittie et al 2012; Garofalo et al 2014a). Initial results revealed a tendency towards biventricular hypertrophy, right ventricular and atrial dilation, and pericardial effusion (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Radiation-induced damage to the lung and heart is dose- and time-dependent and defined by organ-specific time-to-onset, severity, progression of damage and resolution (Garofalo et al, 2014a). Furthermore, the onset of clinical indices of lung injury initiates administration of trigger-based medical management such as dexamethasone, which can mitigate damage throughout the study duration.…”

Section: Discussionmentioning

confidence: 99%

“…Dexamethasone (Henry Schein Animal Health, Dublin OH) was administered according to IACUC-approved “triggers-to-treat and –stop”, Furosemide (Hospira, Lake Forest, IL 60045) was administered by veterinary prescription only based on response to clinical observations. The administration of corticosteroids may be a confounding factor when analyzing data as they are known to influence the appearance of lung injury and have been suggested to prolong mean survival time and mitigate pleural effusions in mouse models of radiation-induced lung injury and rhesus macaques (Gross 1980; Gross et al 1988; Garofalo et al 2014a; Garofalo et al 2014c; Geraci et al 1992). …”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Evolving Mcart Multimodal Imaging Core

Faria¹,

Barrow²,

Ruehle³

et al. 2015

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Computed Tomography (CT) and Echocardiography (EC) are two imaging modalities that produce critical longitudinal data that can be analyzed for radiation-induced organ-specific injury to the lung and heart. The Medical Countermeasures Against Radiological Threats (MCART) consortium has a well-established animal model research platform that includes nonhuman primate (NHP) models of the acute radiation syndrome and the delayed effects of acute radiation exposure. These models call for a definition of the latency, incidence, severity, duration, and resolution of different organ-specific radiation-induced subsyndromes. The pulmonary subsyndromes and cardiac effects are a pair of inter-dependent syndromes impacted by exposure to potentially lethal doses of radiation. Establishing a connection between these will reveal important information about their interaction and progression of injury and recovery. Herein, we demonstrate the use of CT and EC data in the rhesus macaque models to define delayed organ injury thereby establishing: a) consistent and reliable methodology to assess radiation-induced damage to the lung and heart, b) an extensive database in normal age-matched NHP for key primary and secondary endpoints, c) identified problematic variables in imaging techniques and proposed solutions to maintain data integrity and d) initiated longitudinal analysis of potentially lethal radiation-induced damage to the lung and heart.