Dataset Information

Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

ABSTRACT: Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.

SUBMITTER: Byrum SD

PROVIDER: S-EPMC5370149 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

Byrum Stephanie D SD Burdine Marie S MS Orr Lisa L Mackintosh Samuel G SG Authier Simon S Pouliot Mylene M Hauer-Jensen Martin M Tackett Alan J AJ

PloS one 20170328 3

Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In o ...[more]

PMID: 28350824

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Project description:Nuclear accidents and acts of terrorism have the potential to expose thousands of people to high-dose total-body iradiation (TBI). Those who survive the acute radiation syndrome are at risk of developing chronic, degenerative radiation-induced injuries [delayed effects of acute radiation (DEARE)] that may negatively affect quality of life. A growing body of literature suggests that the brain may be vulnerable to radiation injury at survivable doses, yet the long-term consequences of high-dose TBI on the adult brain are unclear. Herein we report the occurrence of lesions consistent with cerebrovascular injury, detected by susceptibility-weighted magnetic resonance imaging (MRI), in a cohort of non-human primate [(NHP); rhesus macaque, Macaca mulatta] long-term survivors of high-dose TBI (1.1-8.5 Gy). Animals were monitored longitudinally with brain MRI (approximately once every three years). Susceptibility-weighted images (SWI) were reviewed for hypointensities (cerebral microbleeds and/or focal necrosis). SWI hypointensities were noted in 13% of irradiated NHP; lesions were not observed in control animals. A prior history of exposure was correlated with an increased risk of developing a lesion detectable by MRI (P = 0.003). Twelve of 16 animals had at least one brain lesion present at the time of the first MRI evaluation; a subset of animals (n = 7) developed new lesions during the surveillance period (3.7-11.3 years postirradiation). Lesions occurred with a predilection for white matter and the gray-white matter junction. The majority of animals with lesions had one to three SWI hypointensities, but some animals had multifocal disease (n = 2). Histopathologic evaluation of deceased animals within the cohort (n = 3) revealed malformation of the cerebral vasculature and remodeling of the blood vessel walls. There was no association between comorbid diabetes mellitus or hypertension with SWI lesion status. These data suggest that long-term TBI survivors may be at risk of developing cerebrovascular injury years after irradiation.

Project description:In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. In such a scenario, minimally invasive biomarkers that can accurately quantify radiation exposure would be useful for triage management by first responders. In this murine study, we evaluated the efficacy of a novel combination of radiation responsive proteins, Flt3 ligand (FL), serum amyloid A (SAA), matrix metalloproteinase 9 (MMP9), fibrinogen beta (FGB) and pentraxin 3 (PTX3) to predict the received dose after whole- or partial-body irradiation. Ten-week-old female C57BL6 mice received a single whole-body or partial-body dose of 18 Gy from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected by cardiac puncture at 24, 48, 72 h and 1 week postirradiation. Plasma protein levels were determined via commercially available ELISA assay. A multivariate discriminant analysis was utilized to generate best-fit dose prediction models for whole-body exposures using the selected biomarker panel and its potential application to partial-body exposures was examined. The combination of values from FL, SAA, MMP9, FGB and PTX3 between 24 h and 1 week postirradiation yielded novel dose-response relationships. For day 1 postirradiation, the best-fit model yielded a predictive accuracy of 81% utilizing FL alone. The use of additional proteins did not enhance the model accuracy whereas, at day 2 postirradiation, the addition of PTX3 and FGB to FL increased the accuracy to 100%. At day 3 the use of FL and PTX3 yielded a predictive accuracy of 93% and at day 7 use of FL and SAA had an accuracy of 90%. Dose prediction of partial-body exposures based on the TBI model had a higher predictive accuracy when the percentage of the body exposed to radiation increased. Our findings indicate that this novel combination of radiation responsive biomarker proteins are an efficient method for predicting radiation exposure and are more accurate when used in concert compared to using any single biomarker protein alone.

Project description:Threats of nuclear terrorism coupled with potential unintentional ionizing radiation exposures have necessitated the need for large-scale response efforts of such events, including high-throughput biodosimetry for medical triage. Global metabolomics utilizing mass spectrometry (MS) platforms has proven an ideal tool for generating large compound databases with relative quantification and structural information in a short amount of time. Determining metabolite panels for biodosimetry requires experimentation to evaluate the many factors associated with compound concentrations in biofluids after radiation exposures, including temporal changes, pre-existing conditions, dietary intake, partial- vs. total-body irradiation (TBI), among others. Here, we utilize a nonhuman primate (NHP) model and identify metabolites perturbed in serum after 7.2 Gy TBI without supportive care [LD70/60, hematologic (hematopoietic) acute radiation syndrome (HARS) level H3] at 24, 36, 48 and 96 h compared to preirradiation samples with an ultra-performance liquid chromatography quadrupole time-of-flight (UPLC-QTOF) MS platform. Additionally, we document changes in cytokine levels. Temporal changes observed in serum carnitine, acylcarnitines, amino acids, lipids, deaminated purines and increases in pro-inflammatory cytokines indicate clear metabolic dysfunction after radiation exposure. Multivariate data analysis shows distinct separation from preirradiation groups and receiver operator characteristic curve analysis indicates high specificity and sensitivity based on area under the curve at all time points after 7.2 Gy irradiation. Finally, a comparison to a 6.5 Gy (LD50/60, HARS level H2) cohort after 24 h postirradiation revealed distinctly increased separations from the 7.2 Gy cohort based on multivariate data models and higher compound fold changes. These results highlight the utility of MS platforms to differentiate time and absorbed dose after a potential radiation exposure that may aid in assigning specific medical interventions and contribute as additional biodosimetry tools.

Project description:CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.

Dataset Information

Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

Publications

Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

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