Gamma-Tocotrienol Modulates Total-Body Irradiation-Induced Hematopoietic Injury in a Nonhuman Primate Model

Abstract

Radiation exposure causes acute damage to hematopoietic and immune cells. To date, there are no radioprotectors available to mitigate hematopoietic injury after radiation exposure. Gamma-tocotrienol (GT3) has demonstrated promising radioprotective efficacy in the mouse and nonhuman primate (NHP) models. We determined GT3-mediated hematopoietic recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques divided into two groups received either vehicle or GT3, 24 h prior to TBI. Four animals in each treatment group were exposed to either 4 or 5.8 Gy TBI. Flow cytometry was used to immunophenotype the bone marrow (BM) lymphoid cell populations, while clonogenic ability of hematopoietic stem cells (HSCs) was assessed by colony forming unit (CFU) assays on day 8 prior to irradiation and days 2, 7, 14, and 30 post-irradiation. Both radiation doses showed significant changes in the frequencies of B and T-cell subsets, including the self-renewable capacity of HSCs. Importantly, GT3 accelerated the recovery in CD34+ cells, increased HSC function as shown by improved recovery of CFU-granulocyte macrophages (CFU-GM) and burst-forming units erythroid (B-FUE), and aided the recovery of circulating neutrophils and platelets. These data elucidate the role of GT3 in hematopoietic recovery, which should be explored as a potential medical countermeasure to mitigate radiation-induced injury to the hematopoietic system.

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

“…On the contrary, in our TBI study, we observed that GT3 treatment increased CFU-GM from day 7 onwards (40). Taken together, these results further confirm the earlier published studies in mice and NHPs that show GT3 is highly competent in protecting the hematopoietic tissue by facilitating/inducing HPCs recovery (34,35,40), and thereby promoting radiation-induced reduction in BM hematopoiesis.…”

“…Likewise, in our current study, NHPs exposed to the same dose with PBI showed an accelerated recovery of CFU-GM in GT3-treated groups, noted as early as day 2, suggesting sparing of BM might have facilitated the recovery process. On the contrary, in our TBI study, we observed that GT3 treatment increased CFU-GM from day 7 onwards (40). Taken together, these results further confirm the earlier published studies in mice and NHPs that show GT3 is highly competent in protecting the hematopoietic tissue by facilitating/inducing HPCs recovery (34,35,40), and thereby promoting radiation-induced reduction in BM hematopoiesis.…”

“…6H). On the contrary, we observed a general increase in the frequencies of T cells, T H cells, and T C cells on days 2, 7 and 14 in both vehicle-and GT3treated groups exposed to 5.8 Gy TBI (40). Furthermore, no significant change was observed in Treg cells in either vehicle-or GT3-treated groups at 5.8 Gy PBI (Fig.…”

“…The site for BM collection was the iliac crest and the site was alternated between collection days. This procedure was conducted by trained study personnel as described earlier ( 40 ). For pain management, a single dose of buprenorphine ([0.005–0.03 mg/kg, intramuscularly (im) or sc] was administered.…”

“…Most importantly, GT3 is under advanced development as a radioprotective MCM following the U.S. FDA Animal Rule to be used as a pre-exposure prophylaxis for H-ARS ( 31 ). Notably, in a recent study, we showed that GT3 accelerated recovery in CD34 + cells which increased HSC function as evidenced by improved recovery of CFU-GM and burst-forming units-erythroid (BFU-E), and enhanced the recovery of circulating neutrophils and platelets in an NHP model of 4 and 5.8 Gy TBI ( 40 ).…”