Early hematopoiesis inhibition under chronic radiation exposure in humans

The major goal of this study was to identify and quantitatively describe the association between the characteristics of chronic (low-dose rate) exposure to (low LET) ionizing radiation and cellularity of peripheral blood cell lines. About 3,200 hemograms (i.e., spectra of blood counts) obtained over the years of maximal exposure to ionizing radiation (1950–1956) for inhabitants of the Techa River were used in analyses. The mean cumulative red bone marrow dose (with standard errors), calculated using Techa River Dosimetry System-2000, was 333.6 ± 4.6 mGy (SD = 259.9 mGy, max = 1151 mGy) to the year 1956. The statistical approach included both empirical methods for estimating frequencies of cytopenic states of the investigated blood cell lines (e.g. neutrophile, platelets, erythrocyte, etc.), and regression methods, including generalized linear models and logistic regressions which allowed taking into account confounding factors (e.g., attained age, age at maximal exposure, presence of concomitant diseases, and demographic characteristics). The results of the analyses demonstrated hematopoiesis inhibition manifested by a decrease in peripheral blood cellularity and an increase in the frequency of cytopenia in all blood cell lines (leukocytes, including lymphocytes, monocytes, neutrophiles, as well as platelets and erythrocytes). The intensity of hematopoiesis inhibition in the period of maximal exposures is determined by the combined influence of the dose rate and cumulative dose. The contribution of specific confounding factors was quantified and shown to be much less important than dose characteristics. The best predictor among dose characteristics was identified for each blood cell line. A 2-fold increase in dose rate is assumed to be a characteristic of radiosensitivity and a quantitative characteristic of the effect.     

Experimental and theoretical study of the dynamics of lymphopoiesis during prolonged irradiation

A mathematical model has been developed describing the dynamics of lymphopoiesis in mammals chronically exposed to ionizing radiation: it is based on the chalone mechanism of regulation of the rate of bone marrow blast cell reproduction and represents a system of 9 nonlinear differential equations. The results of the mathematical simulation and experimental evidence have been found to agree within a wide range of dose rates.     

Global dynamics of hematopoietic stem cells and differentiated cells in a chronic myeloid leukemia model

We consider a mathematical model describing evolution of normal and leukemic hematopoietic stem cells (HSC) and differentiated cells in bone marrow. We focus on chronic myeloid leukemia (CML), a cancer of blood cells resulting from a malignant transformation of hematopoietic stem cells. The dynamics are given by a system of ordinary differential equations for normal and leukemic cells. Homeostasis regulates the proliferation of normal HSC and leads the dynamics to an equilibrium. This mechanism is partially efficient for leukemic cells. We define homeostasis by a functional of either hematopoietic stem cells, differentiated cells or both cell lines. We determine the number of hematopoietic stem cells and differentiated cells at equilibrium. Conditions for regeneration of hematopoiesis and persistence of CML are obtained from the global asymptotic stability of equilibrium states. We prove that normal and leukemic cells can not coexist for a long time. Numerical simulations illustrate our analytical results. The study may be helpful in understanding the dynamics of normal and leukemic hematopoietic cells.     

Status of hemapoiesis in residents of the Techa riverside villages in the period of maximum radiation exposure. Report 2. Influence of exposure dose and dose rate of red bone marrow as well as modifying factors on the frequency of cytopenia and cytosis

The purpose of this study is a retrospective estimation of the influence of dose and dose rate of the red bone marrow chronic radiation exposure in combination with various modifying factors (gender, age, comorbidity) on the frequency of deviations from normal values of the results of peripheral blood investigation in humans exposed on the Techa River. The results of investigation show that humans chronically exposed to radiation can develop marked changes in the cellular composition of peripheral blood characterized by a tendency to cytopenia (signs of the decompensation of hemopoiesis). The tendency to cytopenia can be identified earlier in the lymphoid germ, and later in platelet and erythroid lines. A high lability of granulocytes under the influence of various, often infectious, factors is the cause of the lack of statistically significant differences in terms of frequency of neutropenia. Several non-radiation factors (gender, age, health status) in combination with radiation exposure could have a modifying influence on hematopoiesis, which contributed to the disruption of adaptation processes and the development of conditions characterized by a tendency to cytopenias in exposed individuals. The red bone marrow dose rate reduction resulted in a gradual decrease in the frequency of erythrocytopenia, thrombocytopenia, neutropenia and lymphocytopenia in the group of exposed population. Increased frequencies of erythrocytosis, thrombocytosis, lymphocytosis, monocytosis and neutrophilia were observed when the median dose rate was reduced to the level of 0.024 Gy/year (in the year 1956), which could be regarded as activation of regenerative processes in hematopoiesis.     

Adaptive response of blood lymphocytes as a marker of hemopoiesis status in exposed persons

An obvious correlation between the type of reaction manifested by peripheral blood lymphocytes to low dose irradiation in vitro (adaptive potential), the RBM cell composition (during the period of the major exposure), and the peripheral blood cell composition (at a late time period coincident with the studies of induced radioresistance) has been found in the Techa riverside residents in the later periods after the onset of a long-term low-dose rate radiation exposure (55-60 years later) within a range of individual red bone marrow doses from 0.01 to 1.79 Gy. The nature of these dependences observed in chronically exposed individuals differs from that revealed in the controls. It can be suggested based on the results of the study that the capacity for the adaptive response shown by peripheral blood lymphocytes donated by exposed persons in the remote period after exposure can be regarded as a biological marker of the functional state of the hemopoietic stem cell pool.     

Prediction of the changes in thermodynamic stability of proteins caused by single amino acid substitutions

The functional (synthetic) activity of blood lymphocytes and bone marrow hematopoietic cells in ground squirrels was studied in different seasons and at different stages of the torpor-arousal cycle. The effect of γ-irradiation on animals in different physiological states was also studied. The synthetic activity of cells was estimated from the amount of active RNA per unit DNA in the cell (parameter α). The α values in lymphocytes were minimal in hibernating animals (January–March), reached a peak upon their complete awakening (April), slightly decreased in the summer activity period, and decreased further in the prehibernation autumn period (November). During winter arousals between torpor bouts, this parameter reached the same values as in summer. The dynamics of parameter α in bone marrow hematopoietic cells were generally similar: minimal values in November and higher between torpor bouts than in summer. The peak of synthetic activity of proliferating hematopoietic cells recorded upon awakening from hibernation in April was mainly due to the accumulation of cells in the G₁ and G₂ phases of the cell cycle, and its decrease in summer reflected prevalent transition from G₂ to mitosis and then partly to G₀. In the torpor-arousal-euthermia cycle, two stages of awakening were distinguished, differing considerably in most of the test parameters. The synthetic activity and the total number of blood and bone marrow cells in ground squirrels irradiated in the state of torpor did not differ significantly from those in nonirradiated torpid animals. The adverse effect of radiation in animals irradiated at the initial stage of awakening was lesser than in animals irradiated in the active state, whereas animals at the second stage of awakening proved more vulnerable to acute irradiation. The physiological state of ground squirrels exposed to ionizing radiation at different phases of the torpor-arousal-euthermia cycle plays a key role in the dynamics of qualitative and quantitative characteristics of blood system cells. The results of this study indicate that the hypometabolic state of ground squirrels during hibernation is a factor of protection from the impact of ionizing radiation on the whole body and on the immune system in particular.     

全身放疗在造血干细胞移植中的研究进展

全身照射疗法(TBI)是一种姑息治疗,该方法已经成功地应用在慢性淋巴细胞白血病或滤泡性淋巴瘤等无干细胞支持的放射敏感的疾病中。目前,在血液系统恶性疾病中造血干细胞移植是较为有效的治疗手段之一,其中全身放射治疗与大剂量化疗是造血干细胞移植疗法的经典预处理方案。TBI方法主要应用在造血移植环境中,具有较强的周期非特异性抗肿瘤效应和免疫抑制效能。TBI给予干细胞移植病人超过正常骨髓的辐射耐受量,通过重建病人的造血和免疫来达到治疗目的。     

The state of hemopoiesis under conditions of long-term bone marrow irradiation in residents of the Techa riverside villages

The paper presents the results of a 50-year study on the state of hemopoiesis in the Techa riverside residents chronically exposed to radiation in the range from low to intermediate doses. The highest bone marrow doses were attributable to intakes of osteotropic 9OSr with drinking water and local food products. During the period of maximum radiation exposures (1951-1953) exposed residents were manifesting decreased counts of peripheral blood leukocytes (neutrophils and lymphocytes) and thrombocytes. Normal counts of erythrocytes were maintained owing to the effect of sufficient compensatory mechanisms, including accelerated rates of erythrocaryocyte proliferation and maturation. The development of peripheral blood granulocytopenia was influenced by the delay in the differentiation of neutrophilic bone-marrow granulocytes at the myelocyte phase, a marked increase in the frequency of lethal abnormalities in bone-marrow neutrophils, and pathological mitoses. The period of normalization of the blood cell composition was significantly variable for different blood cell series, and was noted to depend on exposure dose rate, extent of the primary hemopoiesis inhibition and specific physiological characteristics of exposed individuals.     

Cell Composition of Peripheral Blood in Residents of the Techa River Region Exposed to Radiation in Utero

Biology Bulletin - The results of a study on the composition of peripheral blood cells in residents of the Techa River region (Chelyabinsk oblast) who were exposed to radiation both in utero and...     

Mortality in the offspring of individuals living along the radioactively contaminated Techa River: a descriptive analysis

From 1949 onwards, radioactive waste was released into the Techa River in the southern Urals and the population living along the river was exposed to ionising radiation. Relocation of these people did not start until several years later, causing many individuals to be exposed to substantial doses from internal and external radiation. The identification and follow-up of the exposed individuals started more than 40 years ago and is still continuing. The Techa River offspring cohort (TROC) that has recently been established, comprises 10,459 children born to at least one parent living along the Techa River during the period 1950-1992. Of these children, 3,897 were born during the period of highest release, i.e. between 1950 and 1956 and might thus have been exposed in utero. A total of 1,103 individuals have since died mainly due to infectious and respiratory diseases, injury and poisoning. Only 25 cases were identified as having died of a malignant condition. The radioactive contamination of the Techa River in the southern Urals gives a unique possibility to study the adverse effects of protracted exposure to ionising radiation in a large well-described cohort. The Techa River offspring cohort will make it possible to study the effects on those exposed in utero or early in life and the follow-up of the cohort in the future is, therefore, of great importance. Comparisons with other cohorts of humans exposed early in life, will increase our knowledge in this field of research.     

Parathyroid hormone (PTH) and hematopoiesis: new support for some old observations

Forty-seven years ago, the parathyroid hormone (PTH) in one injection of Lilly's old bovine parathyroid extract, PTE, was found to greatly increase the 30-day survival of heavily X-irradiated rats when given from 18 h before to as long as 3 h after irradiation but no later. This was the first indication that PTH might stimulate hematopoiesis. Recent studies have confirmed the relation between PTH and hematopoiesis by showing that hPTH-(1-34)OH increases the size of the hematopoietic stem cell pool in mice. The peptide operates through a cyclic AMP-mediated burst of Jagged 1 production in osteoblastic cells lining the stem cells' niches on trabecular bone surfaces. The osteoblastic cells' Jagged 1 increases the hematopoietic stem cell pool by activating Notch receptors on attached stem cells. PTH-triggered cyclic AMP signals also directly stimulate the proliferation of the hematopoietic stem cells. However, the single PTH injection in the early experiments using PTE probably increased the survival of irradiated rats mainly by preventing the damaged hematopoietic progenitors from irreversibly initiating self-destructive apoptogenesis during the first 5 h after irradiation. It has also been shown that several daily injections of hPTH-(1-34)OH enable lethally irradiated mice to survive by stimulating the growth of transplanted normal bone marrow cells. If the osteogenic PTHs currently entering or on the verge of entering the market for treating osteoporosis can also drive hematopoiesis in humans as well as rodents, they could be potent tools for reducing the damage inflicted on bone marrow by cytotoxic cancer chemotherapeutic drugs and ionizing radiation.     

Protracted radiation exposure and cancer mortality in the Techa River Cohort

In the 1950s many thousands of people living in rural villages on the Techa River received protracted internal and external exposures to ionizing radiation from the release of radioactive material from the Mayak plutonium production complex. The Extended Techa River Cohort includes 29,873 people born before 1950 who lived near the river sometime between 1950 and 1960. Vital status and cause of death are known for most cohort members. Individualized dose estimates have been computed using the Techa River Dosimetry System 2000. The analyses provide strong evidence of long-term carcinogenic effects of protracted low-dose-rate exposures; however, the risk estimates must be interpreted with caution because of uncertainties in the dose estimates. We provide preliminary radiation risk estimates for cancer mortality based on 1,842 solid cancer deaths (excluding bone cancer) and 61 deaths from leukemia. The excess relative risk per gray for solid cancer is 0.92 (95% CI 0.2; 1.7), while those for leukemia, including and excluding chronic lymphocytic leukemia, are 4.2 (CI 95% 1.2; 13) and 6.5 (CI 95% 1.8; 24), respectively. It is estimated that about 2.5% of the solid cancer deaths and 63% of the leukemia deaths are associated with the radiation exposure.     

Status of hemapoiesis in residents of the Techa riverside villages in the period of maximum radiation exposure. Report 1. Evaluation of the cellular composition of peripheral blood and the role of comorbidities in the oppression of hemapoiesis

Residents of the Techa riverside villages chronically exposed to ionizing radiation (the average dose rate in 1951-1956 was 0.047 Gy/year, the maximum reached 2.44 Gy/year) developed marked changes in the cellular composition of peripheral blood. The maximum reduction of peripheral blood counts occurred in the years 1951-1953, after which the beginning of the restoration of cellularity to the control level was observed. The dose rate at this point (1956) was about 0.02 Gy/year. The factors of radiation and non-radiation nature (gender, the age at the onset of exposure, health related disorders) in different combinations affect the number of peripheral blood cells. The influence of dose rate of a chronic radiation exposure on a platelet count takes precedence over other factors. The factors of gender and dose rate determine the number of erythrocytes in exposed persons. The changes accompanying the health status and dose rate significantly affect the number of neutrophils. The influence of comorbidity, age and dose rate on the number of monocytes was noted. A lymphocyte count was mainly determined by the age at the onset of exposure and concomitant diseases. A joint influence of chronic radiation exposure and concomitant diseases increases a mutual action on erythro- and thrombocytopoiesis. The decrease of the dose rate was followed by a gradual predominance of the somatic disease influence on leukocyte (neutrophils, lymphocytes and monocytes) counts.     

Characterization of immunity status in exposed residents of the Techa riverside villages 50 years after the onset of radiation exposure

The goal of the study was to assess the state of immunity in exposed residents of the Techa riverside villages 50 years, or more, after the onset of radiation exposure. 127 chronically exposed persons and 55 unexposed persons were studied. The mean dose to red bone marrow (RBM) was 0.69 Sv in exposed subjects, the mean dose to soft tissue was 0.07 Sv, the mean dose rate amounted to 0.10 Sv/yr to RBM and 0.02 Sv/yr to soft tissues in 1950. The state of the basic links of the immunity system (cellular, humoral, mononuclear phagocyte system, cytokine spectrum, etc.) was assessed using conventional methods. Exposed persons manifested a significant reduction in the absolute counts of CD3+, CD4+, CD 11b+, CD16+ lymphocytes in the peripheral blood, as well as an increase in the relative counts of CD8+. The group comprised of the Techa riverside residents demonstrated an increased immunoregulatory index (exposed individuals: 1.47; controls: 1.71, p = 0.001). An increased production of Immunoglobulin A and increased proportions of CD25+ lymphocytes were revealed in exposed individuals. Changes in the phagocytic activity of neutrophils and monocytes were insignificant, and were primarily associated with changes in the proportions of pagocytes in the peripheral blood stream. The state of the immunity in chronically exposed individuals at late time after the begin of exposure is characterized by a number of specific features reflected primarily on the cellular immunity. No relationship between immunity changes and accumulated exposure dose and dose rate were noted over the period of maximum radiation exposures (1950).     

Hematopoietic cell renewal systems: mechanisms of coping and failing after chronic exposure to ionizing radiation

On the occasion of the first international workshop on systems radiation biology we review the role of cell renewal systems in maintaining the integrity of the mammalian organism after irradiation. First, 11 radiation emergencies characterized by chronic or protracted exposure of the human beings to ionizing irradiation were “revisited”. The data provide evidence to suggest that at a daily exposure of about 10–100 mSv, humans are capable of coping with the excess cell loss for weeks or even many months without hematopoietic organ failure. Below 10 mSv/day, the organisms show some cellular or subcellular indicators of response. At dose rates above 100 mSv/day, a progressive shortening of the life span of the irradiated organism is observed. To elucidate the mechanisms relevant to tolerance or failure, the Megakaryocyte–thrombocyte cell renewal system was investigated. A biomathematical model of this system was developed to simulate the development of thrombocyte concentration as a function of time after onset of chronic radiation exposure. The hematological data were taken from experimental chronic irradiation studies with dogs at the Argonne National Laboratory, USA. The results of thrombocyte response patterns are compatible with the notion of an “excess cell loss” (compared to the steady-state) in all proliferative cell compartments, including the stem cell pool. The “excess cell loss” is a function of the daily irradiation dose rate. Once the stem cell pool is approaching an exhaustion level, a “turbulence region” is reached. Then it takes a very little additional stress for the system to fail. We conclude that in mammalian radiation biology (including radiation medicine), it is important to understand the physiology and pathophysiology of cell renewal systems in order to allow predicting the development of radiation induced lesions.     

Modeling analysis of the lymphocytopoiesis dynamics in chronically irradiated residents of Techa riverside villages

A biologically motivated dynamical model of the lymphocytopoietic system in irradiated humans is applied here to analyze the data obtained under hematological examinations of residents of Techa riverside villages. Those people were exposed to chronic irradiation with varying dose rates, due to the radioactive contamination of the river basin by the Mayak Production Association. Modeling studies revealed the relationship between the dynamics of the lymphocytopoietic system in the examined individuals and the variation of dose rate over the considered period of time. It is found that the developed model is capable of reproducing the decreased level of blood lymphocyte concentration observed during the period of maximum radiation exposure, the recovery processes in the system observed during the period of decreasing dose rate, as well as the enhanced mitotic activity of bone marrow precursor cells in this hematopoietic lineage observed during the entire period under consideration. Mechanisms of these effects of chronic irradiation on the human lymphocytopoietic system are elucidated based on the applied model. The results obtained demonstrate the efficiency of the developed model in the analysis, investigation, and prediction of effects of chronic irradiation with varying dose rate on the human lymphocytopoietic system. In particular, the developed model can be used for predicting any radiation injury of this vital system in people exposed to chronic irradiation due to environmental radiological events, such as anthropogenic radiation accidents or radiological terroristic attacks.     

Mouse and human embryonic stem cell models of hematopoiesis: past, present, and future

Human embryonic stem (ES) cells provide a unique model and an important resource to analyze early hematopoietic development. Other systems to study mammalian hematopoiesis include mouse ES cells, dissection of timed mouse embryos, or use of human postnatal hematopoietic tissue typically isolated from bone marrow or umbilical cord blood. All these models have particular strengths and weaknesses. The extensive studies on murine hematopoiesis provide a basis for work on the human developmental system. Since there are likely some important species differences, use of human ES cells now provides an optimal means to evaluate basic cellular and molecular mechanisms that regulate the beginning stages of human blood development, prior to derivation of hematopoietic stem cells (HSCs). Eventually, research on human ES cells may provide an alternative source of HSCs and other blood products for hematopoietic cell transplantation or other cellular therapies.     

The allometry of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is an acquired neoplastic hematopoietic stem cell (HSC) disorder characterized by the expression of the BCR-ABL oncoprotein. This gene product is necessary and sufficient to explain the chronic phase of CML. The only known cause of CML is radiation exposure leading to a mutation of at least one HSC, although the vast majority of patients with CML do not have a history of radiation exposure. Nonetheless, in humans, significant radiation exposure (after exposure to atomic bomb fallout) leads to disease diagnosis in 3-5 years. In murine models, disease dynamics are much faster and CML is fatal over the span of a few months. Our objective is to develop a model that accounts for CML across all mammals. In the following, we combine a model of CML dynamics in humans with allometric scaling of hematopoiesis across mammals to illustrate the natural history of chronic phase CML in various mammals. We show how a single cell can lead to a fatal illness in mice and humans but a higher burden of CML stem cells is necessary to induce disease in larger mammals such as elephants. The different dynamics of the disease is rationalized in terms of mammalian mass. Our work illustrates the relevance of animal models to understand human disease and highlights the importance of considering the re-scaling of the dynamics that accrues to the same biological process when planning experiments involving different species.     

Characteristics of Myeloid Differentiation and Maturation Pathway Derived from Human Hematopoietic Stem Cells Exposed to Different Linear Energy Transfer Radiation Types

Exposure of hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation causes a marked suppression of mature functional blood cell production in a linear energy transfer (LET)- and/or dose-dependent manner. However, little information about LET effects on the proliferation and differentiation of HSPCs has been reported. With the aim of characterizing the effects of different types of LET radiations on human myeloid hematopoiesis, in vitro hematopoiesis in Human CD34⁺ cells exposed to carbon-ion beams or X-rays was compared. Highly purified CD34⁺ cells exposed to each form of radiation were plated onto semi-solid culture for a myeloid progenitor assay. The surviving fractions of total myeloid progenitors, colony-forming cells (CFC), exposed to carbon-ion beams were significantly lower than of those exposed to X-rays, indicating that CFCs are more sensitive to carbon-ion beams (D ₀ = 0.65) than to X-rays (D ₀ = 1.07). Similar sensitivities were observed in granulocyte-macrophage and erythroid progenitors, respectively. However, the sensitivities of mixed-type progenitors to both radiation types were similar.In liquid culture for 14 days, no significant difference in total numbers of mononuclear cells was observed between non-irradiated control culture and cells exposed to 0.5 Gy X-rays, whereas 0.5 Gy carbon-ion beams suppressed cell proliferation to 4.9% of the control, a level similar to that for cells exposed to 1.5 Gy X-rays. Cell surface antigens associated with terminal maturation, such as CD13, CD14, and CD15, on harvest from the culture of X-ray-exposed cells were almost the same as those from the non-irradiated control culture. X-rays increased the CD235a⁺ erythroid-related fraction, whereas carbon-ion beams increased the CD34⁺CD38⁻ primitive cell fraction and the CD13⁺CD14^+/−CD15⁻ fraction. These results suggest that carbon-ion beams inflict severe damage on the clonal growth of myeloid HSPCs, although the intensity of cell surface antigen expression by mature myeloid cells derived from HSPCs exposed to each type of radiation was similar to that by controls.