Delayed Effects of Acute Radiation Exposure in the Nonhuman Primate Radiation Late Effects Cohort

Studies in the RLEC reveal systemic, multi-organ complications associated with DEARE, including persistent metabolic, musculoskeletal, pulmonary, and neurological dysfunction. Lee et al. observed continuing skeletal muscle dysfunction in male rhesus macaques after an average of four years of follow-up when compared to naive controls. Among this cohort, TBI-induced insulin resistance was associated with impaired insulin receptor signaling in skeletal muscle. Additional analysis by Mohamed et al. revealed the long-term impacts of TBI on joint health, including observed decreases in cortical volume and bone mineral density, as well as shorter humeral length, all of which could contribute to long-term metabolic dysfunction. The development of DEARE-lung, including chronic pulmonary fibrosis, is associated with high morbidity due to reduced respiratory capacity. In this issue, Schaaf et al. found that senescence-associated secretory phenotypes in bronchoalveolar lavage fluid may be an early predictor of fibrotic outcomes in the lung. Finally, Johnson et al. documented neurological complications such as vascular damage, neuroinflammation, and white matter injury among the RLEC. Taken together, studies among the RLEC are helping to define the multi-organ effects associated with DEARE.

One of the biggest concerns in the event of an unanticipated radiological incident is the ability to distinguish between those that need immediate medical support, those whose care can be delayed, and “concerned citizens”, who do not require care but do need reassurance. Rapid and accurate individual biodosimetry assessments are necessary to support medical professionals in making informed treatment decisions. With this goal in mind, NIAID sponsored a large collaborative study where a variety of biospecimen types were collected over a period of 60 days from an irradiated animal cohort and samples were distributed across multiple. Utilizing various omic technologies, investigators independently identified multiple biosignatures that were enriched for pathways relevant to acute radiation injury institutions (McDonald et al.). Follow-up analysis of urine and serum samples from the same animals over two years showed that metabolic fingerprints due to radiation exposure remained persistently altered (Laiakis et al.). The discovered biomarkers from this study are not only helpful in facilitating treatment for acute illnesses but also in predicting late health effects that can benefit from early intervention.

The importance and contribution of studies examining NHP responses to radiation cannot be overstated, especially in terms of understanding acute and delayed injuries, as well as identifying targets and testing medical countermeasures to save human lives. Further, the sustained availability of irradiated NHP survivors (and age-matched, unirradiated control animals) for study in the unique Wake Forest RLEC will continue to provide critical insight into the natural history of radiation exposure in an animal model that best simulates anticipated human responses. The availability of data and samples from this invaluable collection of animals will continue to advance research in multiple fields of radiation biology and contribute to life-saving therapies in areas such as oncology and emergency preparedness.

As the bone marrow compartment is one of the most sensitive organ systems to radiation, leading to changes in nearly all hematopoietic cell lineages, it is not surprising that many hematopoietic-focused studies have been conducted in NHPs to better understand the natural history of radiation exposures and their impact on hemostasis and long-term immunity. Much work has been done to assess and address the immediate neutropenia and thrombocytopenia that result from highdose irradiation, with the development and subsequent licensure of both neutrophil and platelet-promoting products repurposed from other clinical indications. These advances would not have been possible without information gleaned from large animal studies carried out in the rhesus macaque species (primarily of Chinese origin). Identifying longitudinal and dose-dependent outcomes in cellular responses, chronic inflammatory states, and late disease development in these valuable animals, as well as how these biomarkers might differ based on sex and age, forms the basis for understanding human outcomes and risk (Chino et al.). Recent findings highlighted in this special issue are now also helping explain different aspects of bone marrow damage and related outcomes, such as lymphopenia and immune memory deficits. Specifically, studies by Macintyre et al. on pediatric NHPs investigating thymic responses to whole-thorax irradiation have demonstrated how radiation disrupts T cell function, resulting in both immediate and long-term adverse immune effects. Their imaging and histopathology analyses revealed changes in thymic structure, decreased output, and other modifications affecting the health and resilience of these animals. Extending this research, Stover et al. report that acute TBI can result in persistent changes in both T and B cell populations, potentially impairing the animal’s ability to respond to diseases. They studied this by examining measles responses in NHPs vaccinated before irradiation. In vitro challenge tests, where cells were stimulated with measles antigens, showed no impact of radiation on CD8 T cell responses. However, alterations in CD4 populations and cytokine responses were observed, indicating that radiation-induced changes in these adaptive immune cells can modify immune memory, at least for measles, which remains a societal concern.

The first paper in this issue by Cline et al. provides an overview of the RLEC, including a graphical summary of the living animals in the cohort, including the population’s age, sex and radiation dose characteristics; a tabular summary of radiation exposure geometry, dose, dose rate and acute supportive care; mitigator classes used for H-ARS treatment; the strategy for clinical disease monitoring; and a brief summary of the major morbidities identified to date. Notably, the RLEC includes a broad range of total-body irradiation (TBI) and partial-body irradiation (PBI), including a subset of survivors exposed to doses exceeding the lethal dose (LD)90; these animals may be especially valuable for understanding the genetic and physiological features of radiation resilience. Nearly 40% of animals were exposed as juveniles, providing a pediatric-equivalent sub-cohort for contrast with exposures occurring later in life. Both male and female animals are included in the cohort, allowing for contrasts of sex differences and evaluation of sex-specific disease outcomes such as endometriosis in females. A particularly valuable feature of the RLEC is presented by Schaaf et al. article, detailing the intensive pathology assessments conducted and the numerous post-mortem findings in animals for the first 18 years of the cohort. Major findings in this work include a significant acceleration of mortality in radiation survivors compared to unirradiated controls; a high prevalence of neoplasms in irradiated animals; and a pattern of chronic inflammation and fibrosis in multiple organs. Expected radiation effects were seen, such as gonadal atrophy, and obesity was less prevalent in irradiated animals. Additional analysis of both in-life and pathology findings by Quillen et al. demonstrated that while lifetime incidence of chronic diseases was similar for most disease processes, there was an earlier onset in irradiated animals, potentially representing an “accelerated aging” phenotype. A few specific diseases (diabetes, hypertension, cataracts, neoplasms, endometriosis in females, and testicular atrophy in males) occurred only, or primarily, in irradiated animals. Perhaps the most striking finding in these three papers is the observation that DEARE is a multi-morbidity disease; very few animals had a single disorder; older age groups had a median number of morbidities approaching five, with some animals having as many as 12 comorbid conditions.