Long-lasting alterations of the immune system by ionizing radiation exposure: implications for disease development among atomic bomb survivors

PURPOSE: The immune systems of the atomic-bomb (A-bomb) survivors were damaged proportionately to irradiation levels at the time of the bombing over 60 years ago. Although the survivor's immune system repaired and regenerated as the hematopoietic system has recovered, significant residual injury persists, as manifested by abnormalities in lymphoid cell composition and function. This review summarizes the long-lasting alterations in immunological functions associated with atomic-bomb irradiation, and discusses the likelihood that damaging effects of radiation on the immune system may be involved partly in disease development so frequently observed in A-bomb survivors. CONCLUSIONS: Significant immunological alterations noted include: (i) attrition of T-cell functions, as reductions in mitogen-dependent proliferation and interleukin-2 (IL-2) production; (ii) decrease in helper T-cell populations; and (iii) increase in blood inflammatory cytokine levels. These findings suggest that A-bomb radiation exposure perturbed one or more of the primary processes responsible for T-cell homeostasis and the balance between cell renewal and survival and cell death among naive and memory T cells. Such perturbed T-cell homeostasis may result in acceleration of immunological aging. Persistent inflammation, linked in some way to the perturbation of T-cell homeostasis, is key in addressing whether such noted immunological changes observed in A-bomb survivors are in fact associated with disease development.     

Occupational exposure to ionizing radiation has no effect on T‐ and B‐cell total counts or percentages of helper,cytotoxic and activated T‐cell subsets in the peripheral circulation of male radiation workers

Purpose: To investigate changes in immune cell subsets in the peripheral circulation of a male population occupationally exposed to ionizing radiation.

Materials and methods: Peripheral blood samples were taken from 194 male workers with cumulative exposures of >200?mSv (mean exposure 331.5?mSv, mean age 51 years) and from a reference population of 131 male workers with cumulative exposures of <27.5?mSv (mean exposure 13.9?mSv, mean age 47 years). Samples were analysed by flow cytometry for T‐ and B‐cell total counts and for the T‐cell subset percentages of CD4⁺ (helper T‐cells), CD8⁺ (cytotoxic T‐cells) and CD3⁺/HLA‐DR⁺ (activated T‐cells).

Results: Comparison of the >200 and <27.5?mSv exposure groups using linear regression analysis showed no statistically significant differences between the two groups for T‐cell total count, B‐cell total count or for percentages of the T‐cell subsets CD4⁺, CD8⁺ or CD3⁺/HLA‐DR⁺ and CD4⁺:CD8⁺. However, statistically significant increases in both T‐ and B‐cell total counts were observed within the two exposure groups and data pooled from both groups when non‐smokers (never and ex‐smokers) were compared with current smokers. For pooled data T‐cell total count increased in smokers by 35% (p=0.0001) and B‐cell total count increased by 37% (p=0.0004).

Conclusions: No significant immunological effects were observed in male radiation workers with cumulative exposures of >200?mSv when compared with a reference population with cumulative exposures of <27.5?mSv, although highly significant increases in both T‐ and B‐cell total counts were observed in smokers compared with non‐smokers.     

Low dose radiation induced immunomodulation: Effect on macrophages and CD8+ T cells

Purpose: The aim of the present investigation was to study the effect of fractionated whole body low dose ionizing radiation (LDR) on the functional responses of T lymphocytes, their subpopulations and macrophages.

Materials and methods: C57BL/6 mice were exposed to 4 cGy from a ⁶⁰Co source, at 0.31 cGy/min, at 24 h intervals for 5 days (total dose 20 cGy). Phagocytic activity was measured by flow cytometry using Bioparticles® and nitric oxide generation was estimated by spectrophotometry. Proliferation of lymphocytes in response to concanavalin A (con A) and alloantigens was measured by ³H thymidine incorporation. Expression of cell surface markers was assessed by flow cytometric analysis of antibody labeled cells. Target cell killing by cytotoxic T cells (CTL) generated against allogenic cells was assessed by flow cytometry using PKH26 labeled target cells. Cytokines were estimated by enzyme linked immunosorbent assay.

Results: Exposure to LDR enhanced nitric oxide secretion and phagocytosis. The expression of early activation antigen, CD69, was enhanced in CD8⁺ T lymphocytes concomitant with enhanced proliferation in response to con A. In addition, mixed lymphocyte reaction (MLR) and CTL response were augmented and secretion of interferon gamma (IFN-γ) was suppressed following LDR exposure.

Conclusions: LDR exposure enhanced the function of macrophages and responses of CD8⁺ T cells in C57BL/6 mice.     

Lack of association between acute exposure to ionizing radiationand liver cirrhosis

Purpose: Although previous studies have shown significantly increased risks of liver cirrhosis and chronic liver disease for acute radiation exposure among survivors of the atomic bombings of Hiroshima and Nagasaki, Japan, these studies have not taken into account hepatitis B virus (HBV) infections. Because HBV is associated with both A-bomb radiation and liver cirrhosis, our goal was to investigate the relationship of acute ionizing radiation to liver cirrhosis adjusting for HBV, co-occurring primary liver cancer (PLC), and other potential confounders.

Materials and methods: Using a cross-sectional design and pathology review of a cohort of Japanese atomic-bomb survivors, we found that 213 of 335 (63.6%) subjects with PLC and 55 of 776 (7.1%) subjects without PLC had cirrhosis.

Results: We found no association between acute exposure to A-bomb radiation and liver cirrhosis. The adjusted odds ratio of cirrhosis per Sv liver irradiation was 0.59 (95% confidence interval: 0.27 – 1.27). Cirrhosis risks for the highest tertile of radiation exposure (mean exposure 0.7 Sv) were also not elevated (0.8, 0.26 – 2.12 and 0.2, 0.03 – 0.98 among subjects with and without PLC.

Conclusions: Acute exposure to liver irradiation does not increase risks of liver cirrhosis, regardless of PLC status.     

Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate

Purpose:?Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate.

Materials and methods:?Non-tumour dose, D_nt, defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation.

Results:?An inverse correlation was found between D_nt and dose-rate of the radiation. D_nt increased 20-fold with decreasing dose-rate from 1–10^?8 Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D_nt as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D_nt levels.

Conclusions:?The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters.     

Amifostine enhances recovery and expansion of peripheral FAS/CD95+ T- and NK-cell subpopulations during radiotherapy of patients with head-neck cancer

Purpose:?Experimental studies suggest that the FAS/APO-1/CD95 (cytokine receptor protein TNF-receptor superfamily, member 6) cell surface molecule is involved in the apoptotic effect of radiotherapy. In this study we investigated the role of amifostine in protecting the CD95+ (CD: cluster of differentiation) lymphocytic subpopulation in patients with head and neck cancer undergoing radiotherapy.

Materials and methods:?Using flow-cytometry we examined the expression of FAS/CD95 antigen on CD4+ (helper/inducer T cells), CD8+ (suppressor/cytotoxic T cells) and CD56+ (NK, natural killer) T-lymphocytes of 28 patients with head and neck cancer undergoing radiotherapy (with and without amifostine).

Results:?The numbers of peripheral blood lymphocytes were significantly reduced after treatment from (mean value ± STD error) 1477 ± 129 to 1015 ± 77 for T lymphocytes, 700 ± 70 to 454 ± 38 for CD4, 449 ± 46 to 296 ± 34 for CD8 and, 140 ± 18 to 118 ± 13 for NK, before and after treatment, respectively. CD95 expressing lymphocytes showed a faster recovery rate in patients receiving amifostine. CD95 expressing CD56 lymphocytes increased during radiotherapy in patients receiving daily cytoprotection with amifostine to values higher than the pre-treatment levels (p = 0.004).

Conclusion:?It is suggested that amifostine enhances recovery of T- and NK-lymphocyte subpopulations expressing the CD95 antigen in head-neck cancer patients undergoing RT and may enhance the efficacy of the later by interfering FAS-related immunological pathways.     

Analysis of Common Deletion (CD) and a novel deletion of mitochondrial DNA induced by ionizing radiation

Purpose: In order to identify supportive evidence of radiation exposure to cells, we analyzed the relationship between exposure to ionizing radiation and the induction of deletions in mitochondrial DNA (mtDNA).

Materials and methods: Using human hepatoblastoma cell line, HepG2 and its derivatives, HepG2-A, -89 and -400, established after long term exposure to X-ray, mtDNA deletions were analyzed by polymerase chain reaction (PCR) and real-time PCR after cells were subjected to radiation and genotoxic treatments.

Results: Common Deletion (CD), the most extensively studied deletion of mtDNA, was induced within 24 h after exposure to 5 Gray (Gy) of X-rays and was associated with replication of mtDNA. CD became undetectable several days after the exposure due to the death of cells containing mitochondria within which CD had been induced. Furthermore, we found a novel mtDNA deletion that consisted of a 4934 base-pair deletion (4934del) between nucleotide position 8435 and 13,368. A lower dose of ionizing radiation was required to induce the 4934del than for CD and this was independent of the quality of radiation used and was not induced by treatments with hydrogen peroxide (H₂O₂) and other genotoxic reagents including bleomycin.

Conclusion: CD is induced by ionizing radiation, however, the amount of CD detected at a certain point in time after radiation exposure is dependent on the initial frequency of CD induced and the death rate of cells with mtDNA containing CD. The novel mtDNA deletion found in this study, therefore, will be used to determine whether cells were exposed to ionizing radiation.     

Prior irradiation results in elevated programmed cell death protein 1 (PD-1) in T cells

Purpose: In this study we addressed the question whether radiation-induced adverse effects on T cell activation are associated with alterations of T cell checkpoint receptors.

Materials and methods: Expression levels of checkpoint receptors on T cell subpopulations were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving a single fraction of 1 or 4?Gy of γ-ray. T cell activation associated metabolic changes were assessed.

Results: Our results showed that prior irradiation resulted in significant elevated expression of programmed cell death protein 1 (PD-1) in both CD4+?and CD8+?populations, at all three post-radiation time points. T cells with elevated PD-1 mostly were either central memory or naïve cells. In addition, the feedback induction of PD-1 expression in activated T cells declined after radiation.

Conclusion: Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Recent preclinical and clinical studies have showed that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the programmed death-ligand 1 (PD-L1)/PD-1 axis may potentiate the antitumor response. Understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy.     

Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors

PURPOSE: The well-documented increases in malignant tumours in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including cardiovascular disease, may also have increased in incidence with increasing radiation dose. Given that low-level inflammatory responses are widely accepted as a significant risk factor for such diseases, we undertook a detailed investigation of the long-term effects of ionizing radiation on the levels of the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors. MATERIALS AND METHODS: Blood samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors. Plasma levels of CRP and IL-6 were measured using standard antibody-mediated procedures. Relationships between CRP or IL-6 levels and radiation dose were then investigated by multivariate regression analysis. Blood lymphocytes from each individual were used for immunophenotyping by flow cytometry with murine monoclonal antibodies to CD3, CD4 and CD8. RESULTS: CRP levels were significantly increased by about 31% Gy(-1) of estimated A-bomb radiation (p=0.0001). Higher CRP levels also correlated with age, male gender, body mass index and a history of myocardial infarction. After adjustments for these factors, CRP levels still appeared to have increased significantly with increasing radiation dose (about 28% increase at 1Gy, p=0.0002). IL-6 levels also appeared to have increased with radiation dose by 9.3% at 1Gy (p=0.0003) and after multiple adjustments by 9.8% at 1Gy (p=0.0007). The elevated CRP and IL-6 levels were associated with decreases in the percentages of CD4(+) helper T-cells in peripheral blood lymphocyte populations. CONCLUSIONS: Our results appear to indicate that exposure to A-bomb radiation has caused significant increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and which may lead to increased risks of cardiovascular disease and other non-cancer diseases.     

Comparison of the risks of cancer incidence and mortality following radiation therapy for benign and malignant disease with the cancer risks observed in the Japanese A-bomb survivors

PURPOSES: To compare the radiation-associated relative risks of cancer incidence and mortality in groups exposed to ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions with those in the Japanese A-bomb survivor cancer incidence and mortality data. MATERIALS AND METHODS: Comparison of the excess relative risk coefficients derived from published information for each study with the excess relative risk coefficient in comparable (age at exposure, time since exposure, sex) matched subsets of the Japanese A-bomb survivor cancer incidence and mortality data. RESULTS: Sixty-five studies of persons who have received appreciable doses of ionizing radiation in the course of treatment and for whom there is adequate ascertainment of cancer incidence or mortality are identified, from which 116 cancer-site-specific estimates of excess relative risk are derived. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The most marked discrepancies between the relative risks in the medical series and in the A-bomb survivors are for leukaemia, where 12 of the 17 medical studies have significantly lower relative risks than those observed in the Japanese data. However, the ratio between the relative risks in the medical studies and in the Japanese data tends to diminish with increasing average or maximal therapy dose. This is observed for all cancer sites and is particularly marked for leukaemia. After taking account of cell sterilization and dose fractionation the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilization largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Other factors, such as the differences in underlying cancer risks between the Japanese A-bomb survivors and the medical series, and dose-fractionation effects, may also contribute. CONCLUSIONS: The relative risks of cancer in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions are generally less than those in comparable subsets of the Japanese A-bomb survivor cancer incidence and mortality data. Cell sterilization effects can largely explain the discrepancy between the Japanese and the medical series.     

Role of CD4 and CD8 T-lymphocytes,B-lymphocytes and Natural Killer cells in the prediction of radiation-induced late toxicity in cervical cancer patients

Purpose:?To analyse the role of in vitro radio-induced apoptosis of lymphocyte subpopulations as predictive test for late effects in cervical cancer patients treated with radiotherapy.

Methods and materials:?Ninety-four consecutive patients and four healthy controls were included in the study. Toxicity was evaluated using the Late Effects Normal Tissue-Subjective, Objective, Management, and Analytic (LENT-SOMA) scale. Peripheral blood lymphocyte subpopulations were isolated and irradiated at 0, 1, 2 and 8 Gy, and then collected 24, 48 and 72 h after irradiation. Apoptosis was measured by flow cytometry.

Results:?Radiation-induced apoptosis increased with radiation dose and time of incubation, and data fitted to a semi-logarithmic model defined by two constants: α (percentage of spontaneous cell death) and β (percentage of cell death induced at a determined radiation dose). Higher β values in cytotoxic T-lymphocytes (CD8) and bone cells (B-lymphocytes) were observed in patients with low bowel toxicity (hazard ratio (HR)?=?0.96, p?=?0.002 for B-cells); low rectal toxicity (HR?=?0.96, p?=?0.020; HR?=?0.93, p?=?0.05 for B and CD8 subpopulations respectively); low urinary toxicity (HR?=?0.93, p?=?0.003 for B-cells) and low sexual toxicity (HR?=?0.93, p?=?0.010 for CD8-cells).

Conclusions:?Radiation-induced CD8 T-lymphocytes and, for the first time, B-lymphocytes apoptosis can predict differences in late toxicity in cervical cancer patients.     

Activation of immunological network by chronic low-dose-rate irradiation in wild-type mouse strains: Analysis of immune cell populations and surface molecules

Purpose: To analyse the effects of chronic whole body low-dose-rate irradiation on the immune system in various wild-type mouse strains in comparison with the effects from acute high-dose-rate irradiation.

Materials and methods: Wild-type mouse strains (C57BL/6, BALB/c, C3H/He, DBA/1, DBA/2 and CBA) were observed after chronic low-dose-rate γ irradiation at 1.2 mGy hour^?1 by intensive analysis of immune cell populations and their various surface molecules, together with antibody-producing activity both with and without immunization by sheep red blood cells (SRBC). The cell surface functional molecules [cluster of differentiation (CD) 3, CD4, CD8, CD19, CD45R/B220, intercellular adhesion molecule (ICAM)-1, Fas, natural killer (NK)-1.1, chemokine {C-X-C motif } receptor 4 (CXCR4) and chemokine {C-C motif } receptor 5 (CCR5)] and activation molecules [thymocyte-activating molecule (THAM), CD28, CD40, CD44H, CD70, B7-1, B7-2, OX-40 antigen, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD30 ligand and CD40 ligand] were studied in the bone marrow, thymus, spleen, lymph nodes and peripheral blood by flow cytometry.

Results: By chronic low-dose-rate irradiation alone, CD4+ T cells and CD8 molecule expression increased significantly by a maximum of 30%, while CD40+ B cells decreased significantly. Increases of CD4+ T cells, CD40+ B cells and anti-SRBC antibody-producing cells by immunization were significantly enhanced by continuous low-dose-rate irradiation at 1.2 mGy hour^?1. CD3? CD4+ T cells, representative of abnormal immune cells, were absent in the chronically low-dose-rate-irradiated mice, while a dose-dependent increase of these cells was found in acutely high-dose-rate-irradiated mice given the same total doses.

Conclusion: Chronic low-dose-rate radiation activated the immune system of the whole body.     

Occupational exposure to ionizing radiation has no effect on T- and B-cell total counts or percentages of helper, cytotoxic and activated T-cell subsets in the peripheral circulation of male radiation workers

PURPOSE: To investigate changes in immune cell subsets in the peripheral circulation of a male population occupationally exposed to ionizing radiation. MATERIALS AND METHODS: Peripheral blood samples were taken from 194 male workers with cumulative exposures of >200 mSv (mean exposure 331.5 mSv, mean age 51 years) and from a reference population of 131 male workers with cumulative exposures of <27.5 mSv (mean exposure 13.9 mSv, mean age 47 years). Samples were analysed by flow cytometry for T- and B-cell total counts and for the T-cell subset percentages of CD4+ (helper T-cells), CD8+ (cytotoxic T-cells) and CD3+/HLA-DR+ (activated T-cells). RESULTS: Comparison of the >200 and <27.5 mSv exposure groups using linear regression analysis showed no statistically significant differences between the two groups for T-cell total count, B-cell total count or for percentages of the T-cell subsets CD4+, CD8+ or CD3+/HLA-DR+ and CD4+:CD8+. However, statistically significant increases in both T- and B-cell total counts were observed within the two exposure groups and data pooled from both groups when non-smokers (never and ex-smokers) were compared with current smokers. For pooled data T-cell total count increased in smokers by 35% (p=0.0001) and B-cell total count increased by 37% (p=0.0004). CONCLUSIONS: No significant immunological effects were observed in male radiation workers with cumulative exposures of >200 mSv when compared with a reference population with cumulative exposures of <27.5 mSv, although highly significant increases in both T- and B-cell total counts were observed in smokers compared with non-smokers.     

Forthcoming Papers

Summary

A total of 1328 atomic bomb survivors in Hiroshima were studied to determine alterations in the number of blood lymphocytes belonging to T-cell subpopulations, the number of CD19 antigen-positive B cells and the number of Leu 7 and CD16 antigen-positive lymphocytes. Overall, with increasing age, significant decreasing trends in the numbers of some lymphocytes in T-cell subpopulations and of B cells were observed. Furthermore, the number of blood lymphocytes positive for CD5 antigen was significantly lower in the people exposed to radiation (> 1 Gy) in the older age group (more than 30 years old at the time of the bombing). A similar tendency for decreases in the numbers of CD4, CD8, and CD19 antigen-positive cells was observed in these older survivors, although the differences were not statistically significant. These results suggest that aging of the T-cell related immune system is accelerated in the irradiated people of advanced age. This may be explained by the age-related decrease in thymic function in those subjects who were older at the time of the bombing resulting in a decreased functional ability of the immune system after radiation injury. On the contrary, the number of Leu 7 or CD16 antigen-positive cells was found to be increased significantly in the older age group compared to the younger group, although there was little dependence on dose.     

Comparisons of lung tumour mortality risk in the Japanese A-bomb survivors and in the Colorado Plateau uranium miners: support for the ICRP lung model

PURPOSES: To estimate the ratio of risks for exposure to radon progeny relative to low-LET radiation based on human lung cancer data, taking account of possible time and age variations in radiation-induced lung cancer risk. MATERIALS AND METHODS: Fitting two sorts of time- and age-adjusted relative risk models to a case-control dataset nested within the Colorado Plateau uranium miner cohort and to the Japanese atomic (A)-bomb survivor mortality data. RESULTS: If all A-bomb survivors are compared with the Colorado data, there are statistically significant (two-sided p < 0.05) differences between the two datasets in the pattern of the variation of relative risk with time after exposure, age at exposure and attained age. The excess relative risk decreases much faster with time, age at exposure and attained age in the Colorado uranium miners than in the Japanese A-bomb survivors. If only male A-bomb survivors are compared with the Colorado data, there are no longer statistically significant differences between the two datasets in the pattern of variation of relative risk with time after exposure, age at exposure or attained age. There are no statistically significant differences between the male and female A-bomb survivors in the speed of reduction of relative risk with time after exposure, age at exposure or attained age, although there are indications of rather faster reduction of relative risk with time and age among male survivors than among female survivors. The implicit risk conversion factor for exposure to radon progeny relative to the A-bomb radiation in the male survivors is 1.8 x 10(-2) Sv WLM(-1) (95% CI 6.1 x10(-3), 1.1 x 10(-1)) using a model with exponential adjustments for the effects of radiation for time since exposure and age at exposure, and 1.9 x 10(-2) Sv WLM(-1) (95% CI 6.2 x 10(-3), 1.6 x 10(-1)) using a model with adjustments for the effects of radiation proportional to powers of time since exposure and attained age. Estimates of the risk conversion factor calculated using variant assumptions as to the definition of lung cancer in the Colorado data, or by excluding miners for whom exposure estimates may be less reliable, are very similar. The absence of information on cigarette smoking in the Japanese A-bomb survivors, and the possibility that this may confound the time trends in radiation-induced lung cancer risk in that cohort, imply that these findings should be interpreted with caution. CONCLUSIONS: There are no statistically significant differences between the male A-bomb survivors data and the Colorado miner data in the pattern of variation of relative risk with time after exposure and age at exposure. The risk conversion factor is very close to the value suggested by the latest ICRP lung model, albeit with substantial uncertainties.     

Response of human hematopoietic stem and progenitor cells to energetic carbon ions

Purpose:?To characterise the radiation response of human hematopoietic stem and progenitor cells (HSPC) with respect to X and carbon ion irradiation.

Materials and methods:?HSPC from peripheral blood of healthy donors treated with granulocyte-colony stimulating factor (G-CSF) were enriched for the transmembrane glycoprotein CD34 (cluster of differentiation) and irradiated with X rays or carbon ions (29 keV/μm monoenergetic beam and 60-85 keV/μm spread-out Bragg peak), mimicking radiotherapy conditions. Apoptotic cell death, cell cycle progression and the frequency of chromosomal aberrations were determined.

Results:?After radiation exposure no inhibition in the progression of the cell cycle was detected. However, an enhanced frequency of apoptotic cells and an increase in aberrant cells were observed, both effects being more pronounced for carbon ions than X rays, resulting in a relative biological effectiveness (RBE) of 1.4–1.7. The fraction of complex-type aberrations was higher following carbon ion exposure.

Conclusions:?RBE values of carbon ions are low, as expected for radiosensitive cells. The observed frequencies of apoptotic cells and chromosome aberrations in HSPC are similar to those reported for human peripheral blood lymphocytes suggesting that at least with respect to apoptosis and chromosomal aberrations mature lymphocytes reflect the respective radiation responses of their proliferating progenitors.     

自体外周血干细胞动员时骨髓及外周血相关细胞亚群的动态变化研究

目的：探讨自体外周血干细胞动员时，恶性血液病患者的骨髓及外周血CD34^＋和T细胞亚群的动态变化特点。方法：16例拟行自体外周血干细胞移植患者，在应用化疗＋G—CSF方法动员外周血干细胞期间，以流式细胞仪测定骨髓及外周血CD34^＋和T细胞亚群动态变化情况。结果：化疗后应用G—CSF48h后，骨髓中CD34^＋细胞开始明显增加（P〈0．01），在应用G—CSF72h后，外周血中CD34^＋细胞开始明显增加（P〈0．01），96h后，两者达峰值。较未应用G—CSF时差异显著（P〈0．01）。T淋巴细胞亚群比例处于倒置状态且变化不明显（P〉0．05）。结论：恶性血液病患者在应用化疔＋G—CSF方法动员外周血干细胞时，其骨髓及外周血CD34^＋细胞逐渐增加，于96h后达高峰，T细胞亚群变化不明显。     

Prevalence of atherosclerosis in relation to atomic bomb radiation exposure: An RERF Adult Health Study

Purpose: To determine whether exposure to atomic bomb radiation altered the prevalence of asymptomatic atherosclerosis.

Material and methods: In a cross-sectional analysis, we examined aortic arch calcification by plain chest radiography and common carotid artery intima-media thickness (IMT) by ultrasonography among 1804 survivors of the atomic bombing in Hiroshima. We evaluated the association between atherosclerotic changes and radiation exposure, while adjusting for potentially confounding factors.

Results: Multivariate logistic regression analysis showed that aortic arch calcification was significantly associated with radiation exposure (p < 0.05). The odds ratio at 1 Gy was 1.30 (95% confidence interval [CI]: 1.05 – 1.53) for men and 1.31 (95% CI: 1.13 – 1.51) for women. Carotid artery IMT did not vary significantly with radiation dose (p = 0.18).

Conclusion: Radiation dose contributed to the prevalence of aortic atherosclerosis but not carotid artery atherosclerosis in atomic bomb survivors.     

Time‐ and dose‐dependent changes of intracellular cytokine and cytokine receptor profile of Ewing tumour subpopulations under the influence of ionizing radiation

Purpose: Cytokines and their corresponding cell surface receptors are involved in intercellular signalling pathways and in the radioresistance of normal and malignant cells. The aim was the characterization of the expression of intracellular cytokines, their receptors and apoptosis‐associated markers under the influence of radiation.

Materials and methods: Two Ewing tumours were characterized in vitro before and 4, 24 and 72?h after radiation with 5 and 10?Gy, and in vivo 4, 6 and 15 days after radiation with 5 and 30?Gy by five parameter flow cytometry. Direct fluorescence‐conjugated antibodies directed against intracellular cytokines (interferon‐gamma, tumour necrosis factor [TNF]‐alpha, interleukin 1) and their receptors (CD119, CD120a, CD121a) were used. Annexin V and 7‐amino‐actinomycin D were used to identify radiation‐induced apoptosis.

Results: Inter‐ and intra‐individual heterogeneities were identified by the expression of cytokine receptors and the intracellular cytokine profile before radiation. Time‐ and dose‐dependent up‐regulation of the cytokines TNF‐alpha and interleukin 1 were found in vitro. In vivo, an up‐regulation of CD120a and CD121a was detectable on tumour cell subpopulations. For interferon‐gamma and CD119, no changes were seen.

Conclusions: The observed radiation‐induced changes of cytokine and receptor profile are an indication for complex intercellular interactions in view of radioresistance‐associated mechanisms between cell populations within one individual tumour. The observed heterogeneous response on radiation might have therapeutic implications for an individualized therapy based on combined radiation and cytokine modulation, defined by flow cytometric characterization of markers potentially informative for radioresistance.