64. 2011年4月06日 02:25:11: cqRnZH2CUM
あ、一応、あったか
0.35 or 1.2 mGy/h程度を、5週間照射すると免疫系が活性化して寿命が延びるということか確かに、これを人にあてはめられるなら、浪江町程度（～100μSv)なら、寿命が延びるってことになる ただ人だとどうなるか、もっと強い線量だとどうなるかをチェックした方がいいから やはり浪江町の残留男の出番だなｗ Radiat Res. 2005 Apr;163(4):418-23.
Further study of prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice: effects of whole-life irradiation. Ina Y, Sakai K. Low Dose Radiation Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae, Tokyo, 201-8511, Japan.
Abstract MRL-lpr/lpr mice carry a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to multiple severe diseases. In our previous study (Radiat. Res. 161, 168- 173, 2004), chronic low-dose-rate gamma irradiation of mice at 0.35 or 1.2 mGy/h for 5 weeks markedly prolonged the life span, accompanied by immunological activation. This report shows that extension of the irradiation period to the entire life of the mice at the same dose rates improved survival further. The 50% survival time for untreated mice, 134 days, was prolonged to 502 days by 1.2 mGy/h life-long irradiation. Also obtained were a time course and a radiation dose-rate response for the activation of the immune system as indicated by a significant increase in CD4+ CD8+ T cells in the thymus and CD8+ T cells in the spleen and also by a significant decrease in CD3+ CD45R/B220+ cells and CD45R/B220+ CD40+ cells in the spleen. Drastic ameliorations of multiple severe diseases, i.e. total-body lymphadenopathy, splenomegaly and serious autoimmune diseases including proteinuria, and kidney and brain-central nervous system syndromes, were found in parallel with these immunological activations, with lifelong low-dose-rate irradiation being more effective than 5-week irradiation at low dose rates. PMID: 15799698 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/14731073
Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice.
Ina Y, Sakai K. Low Dose Radiation Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae, Tokyo 201-8511, Japan. y-i@criepi.denken.or.jp
Abstract Chronic low-dose-rate gamma irradiation at 0.35 or 1.2 mGy/h prolonged the life span of MRL-lpr/lpr mice carrying a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to severe autoimmune disease. Immunological modifications as indicated by a significant increase of CD8(+) T cells and a significant decrease of CD3(+) CD45R/B220(+) as well as CD45R/B220(+) CD40(+) cells were found in parallel with amelioration of total-body lymphadenopathy, splenomegaly, proteinuria, and kidney and brain syndromes.
http://informahealthcare.com/doi/abs/10.1080/09553000500519808
Activation of immunological network by chronic low-dose-rate irradiation in wild-type mouse strains: Analysis of immune cell populations and surface molecules
2005, Vol. 81, No. 10 , Pages 721-729 (doi:10.1080/09553000500519808) HTML
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Permissions Yasuhiro Ina, DMSc1† and Kazuo Sakai1 1LDRC (Low Dose Radiation Research Center), CRIEPI (Central Research Institute of Electric Power Industry), Komae, Tokyo, Japan
†Correspondence: Yasuhiro Ina, LDRC (Low Dose Radiation Research Center), CRIEPI (Central Research Institute of Electric Power Industry), 2-11-1 Iwado-kita, Komae, Tokyo, 201-8511, Japan, +81 33480 2111, +81 33480 3113 hormesis@yasuhiro-ina-dmsc.jp 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.
Keywords
Chronic low-dose-rate irradiation, immunological network activation, immune cell populations, cell surface molecules, abnormal immune cells, wild-type mouse strains Read More: http://informahealthcare.com/doi/abs/10.1080/09553000500519808 http://yasuhiro-ina-dmsc.jp/profile.html
世界中で公刊発表された 稲 博士の世界初の
低線量率放射線療法
関連の代表的な英文学術論文 全論文とも、 稲 博士が 筆頭著者 兼 代表著者、かつ、
Corresponding Author になっておられ、 論文に関する連絡先も、
全論文とも 稲 博士 宛になっております。 １． Yasuhiro Ina et al., Prolongation of Life Span Associated with Immunological Modification by Chronic Low-Dose-Rate Irradiation in MRL-lpr/lpr Mice. Radiation Research, 161, 168━173 (2004). ２． Yasuhiro Ina et al., Suppression of Thymic Lymphoma Induction by Life-Long Low-Dose-Rate Irradiation Accompanied by Immune Activation in C57BL/6 Mice. Radiation Research, 163, 153━158 (2005). ３． Yasuhiro Ina et al., Further Study of Prolongation of Life Span Associated with Immunological Modification by Chronic Low-Dose-Rate Irradiation in MRL-lpr/lpr Mice ： Effects of Whole-Life Irradiation. Radiation Research, 163, 418━423 (2005).
４． Yasuhiro Ina et al., Activation of Immunological Network by Chronic Low-Dose-Rate Irradiation in Wild-Type Mouse Strains ： Analysis of Immune Cell Populations and Surface Molecules. International Journal of Radiation Biology, 81, 721━729 (2005). |
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65. 2011年4月06日 02:37:37: cqRnZH2CUM
http://www.groenerekenkamer.nl/grkfiles/images/Dr_INA_Rad_Res_lpr2.pdf
RADIATION RESEARCH 163, 418–423 (2005)
q 2005 by Radiation Research Society.
All rights of reproduction in any form reserved.Further Study of Prolongation of Life Span Associated with
Immunological Modification by Chronic Low-Dose-Rate Irradiation in
MRL-lpr/lpr Mice: Effects of Whole-Life Irradiation Yasuhiro Ina1 and Kazuo Sakai Low Dose Radiation Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae, Tokyo, 201-8511, Japan
Ina, Y. and Sakai, K. Further Study of Prolongation of Life
Span Associated with Immunological Modification by Chronic
Low-Dose-Rate Irradiation in MRL-lpr/lpr Mice: Effects of
Whole-Life Irradiation. Radiat. Res. 163, 418–423 (2005). MRL-lpr/lpr mice carry a deletion in the apoptosis-regulating
Fas gene that markedly shortens life due to multiple severe
diseases. In our previous study (Radiat. Res. 161, 168–
173, 2004), chronic low-dose-rate g irradiation of mice at 0.35
or 1.2 mGy/h for 5 weeks markedly prolonged the life span,
accompanied by immunological activation. This report shows
that extension of the irradiation period to the entire life of the
mice at the same dose rates improved survival further. The
50% survival time for untreated mice, 134 days, was prolonged
to 502 days by 1.2 mGy/h life-long irradiation. Also
obtained were a time course and a radiation dose-rate response
for the activation of the immune system as indicated
by a significant increase in CD41 CD81 T cells in the thymus
and CD81 T cells in the spleen and also by a significant decrease
in CD31 CD45R/B2201 cells and CD45R/B2201 CD401
cells in the spleen. Drastic ameliorations of multiple severe
diseases, i.e. total-body lymphadenopathy, splenomegaly and
serious autoimmune diseases including proteinuria, and kidney
and brain-central nervous system syndromes, were found
in parallel with these immunological activations, with lifelong
low-dose-rate irradiation being more effective than 5-week irradiation
at low dose rates. q 2005 by Radiation Research Society INTRODUCTION MRL-lpr/lpr mice, which carry a mutation of the apoptosis-
regulating Fas gene, develop multiple severe diseases
and have a very short life span, thus providing interesting
animal models for experimental therapy (1–7). In our
previous study, we demonstrated a marked prolongation of
the life span of MRL-lpr/lpr mice by 5-week g irradiation
at a low dose rate of 0.35 mGy/h and more effectively at
1.2 mGy/h (8). These life-span prolongations were associated
with immunological activation and amelioration of au-
1 Address for correspondence: Low Dose Radiation Research Center,
Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita,
Komae, Tokyo, 201-8511, Japan.
toimmune diseases. The present study shows a greater effect
of chronic low-dose-rate irradiation continued for almost
the entire life span of the mice, together with the
results of observations completed for the entire life span of
the mice after a 5-week irradiation at low dose rates.
Low-dose radiation induces various effects on living organisms,
including augmentation of immunological functions
(9–17), prevention and cure of diseases (18–22), and
prolongation of life span (23–25). Low-dose radiation activates
immune activity in wild-type and lpr mice as measured
by proliferation of spleen cells to mitogens (11, 13)
and modifies the latency for radiation-induced myeloid leukemia
in CBA/H mice (26). Furthermore, low-dose radiation
increases the latency of spontaneous lymphomas and
spinal osteosarcomas in cancer-prone, radiation-sensitive
Trp53 heterozygous mice (27). Recently, Ootsuyama et al.
(28) reported that MRL-gld/gld mice, which carry a mutation
within the Fas ligand (FasL) and autoimmune diseases
similar to lpr mice (29–35), showed remission of the
diseases after low-dose irradiation, in parallel with a decrease
in the population of splenic CD42 CD82 T cells.
They attributed this effect to augmentation of apoptosis.
We show in this report that both the amelioration of multiple
severe diseases throughout the body and the prolongation
of life span by chronic low-dose-rate irradiation involve
the activation of the immune system.
MATERIALS AND METHODS
Materials and methods used were essentially as described previously
(8).
Animals
Female MRL/MpJUmmCrj-lpr/lpr mice (5 weeks old) were purchased
from Charles River Japan, Inc., Yokohama, and were kept under specificpathogen-
free conditions. All the animals were maintained on a light
schedule from 7:00 to 19:00 and were fed a standard mouse diet CE-2
(Clea Japan, Inc., Tokyo) with water allowed ad libitum. The study was
reviewed by the Institutional Animal Care and Use Committee, and the
mice were treated in accordance with governmental guidelines and the
guidelines of the Central Research Institute of Electric Power Industry
(CRIEPI).
The urine was tested weekly using commercial test strips (Wako Pure
PROLONGATION OF LIFE SPAN BY WHOLE-LIFE IRRADIATION 419
FIG. 1. Prolongation of life span in MRL-lpr/lpr mice with chronic
low-dose-rate g radiation. a: Nonirradiated controls. The survival results
obtained in our previous observation (8) were combined. b: Mice irradiated
with 0.35 mGy/h for 5 weeks. The observations in our previous
report (8) were extended to the entire life span. c: Mice irradiated with
0.35 mGy/h for the whole life span. d: Mice irradiated with 1.2 mGy/h
for 5 weeks. Observation until day 203 (8) was extended to the entire
life span. e: Mice irradiated with 1.2 mGy/h for 521 days. *P , 0.0001
compared to controls. P , 0.0001 for b 2 c, d 2 e, b 2 d, c 2 e and
b 2 e.
Chemical Industries, Ltd., Osaka). Specimens of organs and tissues were
fixed in 10% formalin/PBS solution. After embedding in paraffin, 3-mmthick
sections were prepared, stained with hematoxylin and eosin (H&E),
and examined histologically under a microscope.
Irradiation
Mice were irradiated in a clean irradiation room equipped with a 370
GBq 137Cs g-ray source (Chiyoda Technol Co., Tokyo). The dose rates
were 1.2 and 0.35 mGy/h, respectively, at a distance of 5 and 10 m from
the source as measured by an ionization chamber and glass dosimeter in
2000. The tissue dose rates measured with a glass dosimeter embedded
in a mouse’s abdomen were 0.95 and 0.30 mGy/h at each point as measured
in a separate experiment (36). The mice were irradiated continuously
except for 1 h in the morning on weekdays. Group a mice (n 5
20) were unirradiated and were treated in the same way as the unirradiated
controls (n 5 12) in the previous experiment (8). Group b mice (n
5 12) were irradiated with 0.35 mGy/h for 5 weeks, which is the same
treatment used in the previous study (8), but were observed for the entire
life span. Group c mice (n 5 20) were irradiated at 0.35 mGy/h for the
whole life span. Group d mice (n 5 12) were irradiated with 1.2 mGy/h
for 5 weeks, which is the same treatment used in the previous study (8),
but were observed for the entire life span. Group e mice (n 5 20) were
irradiated at 1.2 Gy for 521 days. The ages of the mice at the start of
continuous irradiation were 5 weeks for Groups c and e, and 7 weeks for
Groups b and d.
Analysis of Immune Cell Status
Single cell suspensions were prepared from the thymus and spleen in
RPMI 1640 medium supplemented with 10% FCS. Immunological
changes were examined in terms of cell surface molecules after analysis
of cell populations. The cell surface functional molecules CD3, CD4,
CD8, CD45R/B220 (B220) and Fas and activation-marker molecule
CD40 were analyzed by flow cytometry.
For immunofluorescence studies, the following monoclonal antibodies
(mAbs) from BD PharMingen (San Diego, CA) were used: purified 2.4G2
mAb (rat IgG2b, k), which recognizes CD16/32 (Fcg III/II receptor) for
FcBlock; fluorescein isothiocyanate (FITC)-conjugated 17A2 mAb (rat
IgG2b, k), which recognizes CD3 molecular complex; FITC-conjugated
GK1.5 mAb (rat IgG2b, k), CD4; R-phycoerythrin (R-PE)-conjugated 53-
6.7 mAb (rat IgG2a, k), CD8a (Ly-2); FITC-conjugated and R-PE-conjugated
RA3-6B2 mAbs (rat IgG2a, k), CD45R/B220 (B220); R-PE-conjugated
Jo2 mAb (hamster IgG, group 2, l), Fas (CD95); R-PE-conjugated
3/23 mAb (rat IgG2a, k), CD40.
The single cell suspensions of thymus and spleen were preincubated
with unlabeled anti-Fcg receptor mAbs for 10 min at 48C to avoid nonspecific
Fc-mediated binding of the labeled antibodies. The cells were
stained with FITC-conjugated mAbs and R-PE-conjugated mAbs simultaneously
for 20 min at 48C. After they were washed, the stained samples
were analyzed using an EPICS XL flow cytometry system (Beckman
Coulter, Inc., Fullerton, CA).
Statistical Analysis
The Kaplan-Meier method was used to estimate the survival curves
and the significance of differences between the percentages of survival
was evaluated by the logrank test. The significance of differences in the
percentages of mice with lymphadenopathy or proteinuria was evaluated
by the x2 test. The weights of spleen and inguinal lymph nodes and the
percentages of cell populations are presented as means 6 standard errors
of the mean. The statistical significance of the differences was evaluated
by the Student’s t test.
RESULTS
Chronic Low-Dose-Rate g Irradiation Prolonged Life
Span
MRL-lpr/lpr mice were continuously g-irradiated at a
low dose rate of 0.35 or 1.2 mGy/h. In our previous study
(8), the mice were irradiated for 5 weeks, beginning at 7
weeks of age, and observed for 203 days. In the present
study, this observation period was extended to the entire
life span, and continuous irradiation was extended throughout
the whole life span for the 0.35-mGy/h group and for
the 1.2-mGy/h group. Figure 1 shows survival of these
groups plotted as a function of time and clearly shows that
the life span of the lpr mice was significantly prolonged by
continuous low-dose-rate irradiation in a dose-rate-dependent
manner (P , 0.0001 for b 2 c, d 2 e, b 2 d, c 2 e
and b 2 e). Table 1 shows the 50% survival time for the
lpr mice irradiated continuously at two different low dose
rates for two different periods together with changes in immunological
parameters at the two low dose rates. The prolongations
of survival are in parallel with immunological
activities, as discussed later.
Chronic Low-Dose-Rate g Irradiation Suppressed
Lymphadenopathy, Splenomegaly, and Kidney and Brain-
Central Nervous System Syndromes
In parallel with the survival study, we examined the effects
of continuous low-dose-rate g irradiation on specific
diseases in the lpr mice, i.e. lymphadenopathy (Figs. 2A
and 3B), proteinuria (Fig. 2B) and splenomegaly (Fig. 3A).
In the nonirradiated controls, these symptoms developed
over time. However, the symptoms were suppressed re420
INA AND SAKAI
TABLE 1
50% Survival Time and Immunological Parameters for MRL-lpr/lpr Mice g-Irradiated
at Low Dose Rates
Group
Dose rate
(mGy/h)
Irradiation
period
(week)
50%
survival
time (days)
Relative immunological parametersa
Thymus
CD41 CD81
T cells
Spleen
CD81
T cells
CD31 B2201
cells
B2201 CD401
cells
a 0 0 134b 1.0 1.0 1.0 1.0
b 0.35 5 159c ― ― ― ―
c 0.35 35 228 1.1 1.9 0.62 0.81
d 1.2 5 301d ― ― ― ―
e 1.2 74 502 1.2 2.2 0.45 0.37
a Measured in 12 mice in each group irradiated for 7 weeks beginning at 5 weeks of age and killed at 12 weeks
of age.
b Identical results from previous (8) and present studies.
c Previous observation (8).
d Previous observation (8) was extended to whole life.
FIG. 2. Development of lymphadenopathy and proteinuria in MRLlpr/
lpr mice over time and its suppression by chronic g irradiation at low
dose rates beginning at 5 weeks of age. Upper curves: nonirradiated mice.
Middle curves: mice irradiated with 0.35 mGy/h. Lower curves: mice
irradiated with 1.2 mGy/h. n 5 10 per point. Panel A: Mice with palpable
inguinal lymph nodes. *P , 0.01, **P , 0.001, ***P , 0.0001 compared
to controls. Panel B: Mice with proteinuria over 30 mg/dl. *P ,
0.05, **P , 0.01, ***P , 0.001, ****P , 0.0001 compared to controls.
markably by continuous low-dose-rate irradiation, and this
suppression was dependent on the dose rate. Furthermore,
the severity of proteinuria in each mouse was reduced by
the low-dose-rate irradiation (data not shown).
We previously demonstrated a remarkable amelioration
of glomerulonephritis in the kidney and hemorrhage and
inflammation in the brain in low-dose-rate-irradiated lpr
mice using histological sections (8). In this study, we again
observed histological amelioration of disease-specific damage
to the kidney and the brain and also so observed that
the whole brain, central nervous system, liver, intestine,
lung, joints, blood vessels and skin in the low-dose-rateirradiated
mice appeared much less affected compared to
the nonirradiated group (data not shown).
Chronic Low-Dose-Rate g Irradiation Increased Immune
Activities
CD41 CD81 T cells in the thymus are very important for
maturation of the immune system in the entire body. The
population of these cells is small in lpr mice. However,
chronic low-dose-rate irradiation significantly increased
these cell populations (Fig. 4 and Table 1). CD81 T cells
are important for the biological defense system. The cell
population in the spleen was low in the nonirradiated mice.
However, chronic low-dose-rate irradiation increased the
cell population significantly (Fig. 5A and Table 1). CD31
CD45R/B2201 (CD31 B2201) cells are cells that attack the
mouse’s own organs and tissues (37). CD45R/B2201
CD401 (B2201 CD401) cells are characteristic in autoimmune
diseases (38). The percentages of these cells in
spleens are very high in the lpr mice. However, these high
levels of abnormal cells were significantly decreased in the
chronic low-dose-rate-irradiated lpr mice. Furthermore,
suppressions of the abnormal cell populations were dependent
on the dose rate (Fig. 5B, C and Table 1). Also noted
was a tendency for an increase in the percentage of CD41
T cells in the spleen after chronic irradiation at a low dose
rate, indicating augmentation of the immune system in the
whole body. Furthermore, no changes in the total cell numbers
in the bone marrow, no injury in the intestine, and no
radiation-induced lymphomas were observed (data not
shown).
DISCUSSION
The present report summarizes results obtained from lifelong
observation of MRL-lpr/lpr mice that were continuPROLONGATION
OF LIFE SPAN BY WHOLE-LIFE IRRADIATION 421
FIG. 3. Suppression of splenomegaly and lymphadenopathy in MRLlpr/
lpr mice by chronic g irradiation at low dose rates from 5 weeks of
age. Upper curves: nonirradiated mice. Middle curves: mice irradiated
with 0.35 mGy/h. Lower curves: mice irradiated with 1.2 mGy/h. n 5
12 per point. Panel A: The weights of the spleen. *P , 0.01, **P ,
0.001, ***P , 0.0001 compared to controls. Panel B: The weights of
the inguinal lymph nodes. *P , 0.0001 compared to controls.
FIG. 5. Changes in immune cell populations in the spleens of MRLlpr/
lpr mice by chronic g irradiation at low dose rates from 5 weeks of
age. Solid curves: mice irradiated with 1.2 mGy/h. Dashed curves: mice
irradiated with 0.35 mGy/h. Dotted curves: nonirradiated mice. n 5 12
per point. Panel A: CD81 T cells. *P , 0.001, **P , 0.0001 compared
to controls. Panel B: CD31 B2201 cells. *P , 0.01, **P , 0.0001 compared
to controls. Panel C: B2201 CD401 cells. *P , 0.05, **P , 0.01,
***P , 0.001, ****P , 0.0001 compared to controls.
FIG. 4. Increases in normal immune cell populations in the thymuses
of MRL-lpr/lpr mice by chronic g irradiation at low dose rates from 5
weeks of age. Upper curve: mice irradiated with 1.2 mGy/h. Middle
curve: mice irradiated with 0.35 mGy/h. Lower curve: nonirradiated
mice. n 5 12 per point. *P , 0.01, **P , 0.001, ***P , 0.0001 compared
to controls.
ously g-irradiated at low dose rates. Previous observations
(8) already indicated a prolongation of the life span of lpr
mice accompanied by amelioration of disease and immune
activation after 5 weeks of irradiation at low dose rates.
The present study includes whole-life observation of these
mice and provides information on the more profound effects
of life-long irradiation that accompany immune activation
over time.
In this study, whole-life g irradiation at low dose rates
significantly prolonged the life span of lpr mice. The radiation
suppressed total-body lymphadenopathy, splenomegaly
and proteinuria together with kidney and brain-central
nervous system syndromes, which are possible causes
of death in these animals. It significantly increased CD41
CD81 T cells in the thymus and CD81 T cells in the spleen,
422 INA AND SAKAI
which indicates activation of the immune system, and decreased
the representative abnormal cell populations, i.e.
CD31 B2201 cells and B2201 CD401 cells. The CD31
B2201 cells are autoreactive to the mouse’s own organs and
tissues throughout the body. The B2201 CD401 cells are
thought to be the major cell population in the progression
of autoimmune diseases.
We believe that the immunological activations in the
chronically low-dose-rate-irradiated mice are highly important
in disease suppression in lpr mice. We believe that the
increase in CD81 T cells may bring about an effective attack
against abnormal cells and suppress the disease-specific
abnormal cell populations, i.e. CD31 B2201 cells and
B2201 CD401 cells. The B2201 CD401 cells in the lowdose-
rate-irradiated lpr mice decreased to the levels of
those cells in normal mice without the lpr mutation, although
the CD31 B2201 cells still existed. We therefore
consider that these decreases explain the amelioration of
severe autoimmune diseases throughout the body.
It appeared that irradiation with 1.2 mGy/h was more
effective than irradiation with 0.35 mGy/h in the prolongation
of life and the enhancement of the immune system.
We think it is necessary to irradiate mice at a higher dose
rate for the full development of immunity and for suppression
of these diseases. An optimum dose rate may exist
beyond the dose-rate range employed in this study.
Furthermore, lpr mice spontaneously develop inflammation
in the cerebral vessels, meninges and choroid plexus
(5, 6). Our previous observations (8) showed that chronic
low-dose-rate irradiation significantly suppressed cerebral
and central nervous inflammation and hemorrhage in lpr
mice, an observation that was confirmed in the present
study (data not shown).
Pathways to apoptosis through non-Fas-mediated mechanisms
may exist in chronically low-dose-rate-irradiated lpr
mice. When Ootsuyama et al. (28) observed the effects of
low-dose radiation in the amelioration of disease in MRLgld/
gld mice, which have a mutation in the Fas ligand, they
explained the effects of such radiation by recovery of the
apoptotic activity as indicated in spleen cells. However, in
this study, we found no significant difference between the
nonirradiated control mice and the low-dose-rate-irradiated
mice in terms of the percentage of thymocytes stained by
propidium iodide, trypan blue and erythrosin B, respectively,
and the expression of phosphatidylserine on the thymocytes.
Furthermore, there was no expression of Fas, the
apoptosis-regulating molecule, on the thymocytes, splenocytes
and lymph node cells (data not shown).
The difference between lpr and gld mutations or between
the dose rates of radiation in the experiments of Ootsuyama
et al. (28) and our experiments may explain the difference
in apoptosis. Therefore, we consider the immunological
modification in the low-dose-rate-irradiated mice to be the
primary reason for increased survival through amelioration
of diseases, although changes in non-Fas-mediated apoptotic
activity might be indirectly involved.
Finally, it is intriguing that immunological activation by
low-dose-rate irradiation may be effective in suppressing
tumor induction. Indeed, we have found suppression of radiation-
induced thymic lymphomas in C57BL/6 mice to
less than half (40%) by continuous low-dose-rate g irradiation
under conditions identical to those in the present study
(39).
In summary, we found ameliorations of multiple severe
diseases, including total-body lymphadenopathy, splenomegaly
and serious autoimmune diseases throughout the
body, including kidney and brain-central nervous system
syndromes, in MRL-lpr/lpr mice chronically irradiated at
low dose rates. The life span of the mice was prolonged
remarkably in parallel with the activation of the immune
system without severe tissue damage. Thus chronic lowdose-
rate irradiation is expected to be useful in the treatment
of certain lymphomas and autoimmune diseases.
ACKNOWLEDGMENTS
We thank Ms. Ikuno Suzuki and Mr. Takeshi Oda for their excellent
technical assistance and animal care. We are also indebted to Dr. Hiroshi
Tanooka for his critical reading of this manuscript and to Dr. Harumi
Ohyama for her helpful discussions.
Received: March 25, 2004; accepted: October 26, 2004
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