Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation

Abstract

Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min-1) resulting in an approximate LD10/60 (n = 5/59). Animals received medical management and hematopoietic and immune cell recovery was assessed (n ≤ 14) through 370 days post exposure. A subset of animals (n ≤ 8) was examined through 700 days. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia and thrombocytopenia resolved within 30 days. Total CD3+ cells μL-1 required 60 days to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 days post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naïve subsets were markedly different. Memory populations were ≥ 100% of normal by day 60; whereas, naïve populations were only 57% normal at 180 days and never fully recovered to baseline post irradiation. Total (CD20+) B cells μL-1 were within normal levels by 77 days post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion and thymopoiesis.

Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells

“…NHP have been used in radiation dose response studies for many decades [ 9 – 11 , 17 , 46 ], focusing on the effects of mitigators on acute radiation syndromes of different organ systems and mortality. However, there have been few studies of the cellular and molecular level changes underlying these broad biological end-points.…”

Characterizing the Natural History of Acute Radiation Syndrome of the Gastrointestinal Tract: Combining High Mass and Spatial Resolution Using MALDI-FTICR-MSI

“…The MCART consortium has developed and characterized animal models that define the incidence, latency, severity and onset of GI-ARS, H-ARS, and MOI involving the kidney, lung, and heart (Farese et al 2012;Jackson et al 2012;Plett et al 2012;Garofalo et al 2014;de Faria et al 2015;Farese et al 2015;Medhora et al 2015;Zhang et al 2015;Cohen et al 2017). Histological, clinical, and analytical techniques were used to interrogate mechanisms of action (MoA) and identify biomarkers of radiation injury following all-cause mortality (Booth et al 2012a;Chua et al 2012;MacVittie et al 2012a;Jones et al 2014a;Jones et al 2014b;Carter et al 2015;Farese et al 2015;Jones et al 2015;Zhang et al 2015;Carter et al 2016;Carter et al 2017;Cohen et al 2017;Jones et al 2017). While these studies have provided vital mechanistic 'pieces of the puzzle' and identified panels of biomarkers that can be used to assess injury and efficacy of a MCM, they cannot inform on the natural history of injury development.…”

Long-Term Recovery of the Adaptive Immune System in Rhesus Macaques After Total Body Irradiation

“…This is consistent with prior observations from lymphopenic mice, humans, and irradiated NHPs. 19,39 Although peripheral expansion can lead to constriction of TCR diversity, 39 we did not observe a significant change in TCR sequence entropy once the memory:naïve cell balance returned to baseline, suggesting any TCR skewing was transient.…”

“…Given these complications, the rhesus macaque nonhuman primate (NHP) model is often used for evaluation of immune function and radiation countermeasures. [19][20][21][22][23] Importantly, the rhesus immune system closely recapitulates that of humans, and NHPs are susceptible to many human pathogens and simian pathogens that are similar to human pathogens. Further, NHPs are inherently susceptible to inflammation-associated morbidities found in humans such as obesity and hypertension.…”