About CNTS - Program: Tokyo 1999 - "Biological Responce of the Immune System to Low Dose Radiation": Shu-Zheng Liu

RSH > Documents > Tokyo 1999 > Shu-Zheng Liu 1999

Biological Responce of the Immune System to Low Dose Radiation

By Shu-Zheng Liu

MH Radiobiology Research Unit
Norman Bethune University of Medical Sciences

The health effect of low level ionizing radiation has been of much concern to the public, the regulatory bodies, government organizations and academic spheres. According to the linear no-threshold (LNT) hypothesis, any minute amount of radiation would increase the cancer risk of the population. Thus it was supposed that all radiation would be harmful. However, such a doctrine has not gained ample evidence from radiobiological and epidemiological studies. On the contrary, data have been accumulating that low dose radiation (LDR) could up-regulate the body's defense and adaptive mechanisms among which LDR-induced up-regulation of immune reactions is a good example. In this presentation the chief manifestations of immunologic stimulation induced by LDR and their implications will be discussed.

Human observations in a high background radiation area (HBRA) in China demonstrated that the immune reactivity and DNA repair synthesis of the peripheral blood lymphocytes from the inhabitants were significantly higher than those in the inhabitants in an adjacent control area (CA) with the exposure rate of the former being 3.6 times as high as that of the latter. The cancer incidence as a whole was found to be lower in HBRA than in CA, the difference being statistically significant for the inhabitants 40-70 years of age, usually considered as the high cancer incidence group. The inhabitants of this age group in HBRA received an excess of accumulated exposure of 71.2 to 124.6 mGy in comparison with those in the same age group in CA.

The animal studies showed that both the innate immunity (macrophage and NK activity) as well as the adaptive immunity (CTL, ADCC activity and PFC reaction of the splenic lymphocytes) were stimulated by whole-body irradiation (WBI) with low doses of X- and g-rays, and this stimulatory effect on immunity occurred mostly with exposure of mice to doses within 0.2 Gy. The mitogenic response of the T lymphocytes was markedly promoted, expressed as significant increase in synthesis of DNA, RNA and proteins. The mechanisms of these changes in immunity following WBI with low doses have been only partially elucidated, so further studies are needed. We suggest that three interrelated aspects be considered. The first is the activation of interactions between the cells within the immune system with special emphasis on the interactions between lymphocytes and accessory cells. The second is the facilitation of the signal transduction in multiple pathways within these cells. And the third one to be considered is the changes in systemic regulation caused by WBI with low dose X-rays that might enhance the immune reactivity. These will be discussed in more detail in a separate presentation in the Workshop on Low Dose Effects of Ionizing Radiation of ICONE-7 following this Symposium.

The implications of the immunological changes following LDR are evident. Since the immune system is evolved in higher animals as an important defense element of the body combating infection and tumor growth, it is natural to conduct experimental studies with an aim at disclosing the relationship between the immune status and tumor growth.

It has been observed that the growth rate and metastasis of implanted tumor cells (Lewis lung cancer and B16 melanoma) were markedly suppressed by LDR (Tables 1 and 2). It was found that LDR enhanced the efficacy of conventional systemic chemotherapy and local radio-therapy of these cancers accompanied with alleviation of the immuno-suppressive effect of the chemotherapeutic agents and local high dose radiation. It is particularly interesting to note that pre-exposure to LDR before each session of the split-dose X-irradiation (1.75 Gy once a week for 4 consecutive weeks) dramatically decreased the occurrence rate of thymic lymphoma in C57BL/6J mice induced by split-dose irradiation (Table 3).

It is apparent that individuals exposed to low level radiation several times above the average would not

Table 1: Effect of low dose radiation on metastasis of i.v. injected cancer cells

Dose, Gy	Lewis lung cancer	B16 melanoma
Sham-irradiated control	84.5 ą13.9^#	125.8 ą 32.1
0.050	16.3 ą 4.5**	44.2 ą 12.9*
0.075	27.3 ą 8.8*	25.0 ą 7.5*
0.100	20.4 ą 4.4**	47.0 ą 11.3*
0.150	26.9 ą 4.5**	54.4 ą 21.6

Pulmonary nodules counted 14d after i.v. injection of 7x10⁵ tumor cells 24 h after WBI; n= 6-8 for Lewis lung cancer data, n=5 for B16 melanoma data. ^#Mean ąSD of pulmonary nodules per mouse; *P<0.05, **P<0.01 vs sham-irradiated control (Adopted from Ju, G.Z. et al, 1995)

Table 2: Effect of low dose radiation on metastasis of i.m. implanted cancer cells

Treatment	Number of mice	Pulmonary nodules	P
Sham-irradiated control	18	41.7 ą 7.4^#
0.075 Gy x 2	11	39.4 ą 13.2	>0.05
0.075 Gy x 4	10	23.5 ą 11.8	<0.01
Mitomycin C, 3mg/kg, i.p.	17	33.8 ą 11.5	>0.05
0.075 Gy + MMC	14	20.3 ą 4.7	<0.01

Treatments were given 10d after i.m. implantation of 1x10⁵ Lewis lung cancer cells and pulmonary nodules were counted on 11d after termination of treatments, Repeated WBI was administered with 3d intervals. MMC was given i.p. 6h after WBI with 0.075 Gy. ^#Mean ą SD of pulmonary nodules per mouse (Adopted from Zhang, Y. et al, 1998)

increase the relative risk of cancer as shown in the long-time observations in areas of high background radiation (Wei, L.X. et al, 1994). And this is also true for nuclear workers in the US (Gilbert, ES et al. 1989) as well as inChina (Sun, S.Q., 1994). Animal studies shown in the present presentation points to the presence of adaptive response in cancer induction (Table 3). Therefore, it is difficult to exclude the presence of a threshold in carcinogenesis with low level radiation.

Existing data suggest that one of the important mechanisms of the suppressive effect of LDR on cancer formation is the up-regulation of immune responses after LDR. It was observed that one month after the combined exposure to LDR with the split-dose irradiation (0.075 Gy 12 h before 1.75 Gy once a week for four consecutive weeks) a series of immunological parameters were up-regulated. Of special interest is the observation that the secretion of IFN-g and TNF-a, which was suppressed after irradiation with 1.75 Gy x 4, was restored to normal when LDR was given before each high dose (Li, X.J. et al, 1999, in press). It is important to note that this is the time for the pre- lymphoma cells to begin to appear in the thymus after the split-dose irradiation (Boniver, J. et al, 1990; Matsudaira, H. et al, 1992). Previous literature indicated that administration of cytokines, such as IFN-g and TNF-a, could prevent the appearance of thymic lymphoma induced by split-dose irradiation (Boniver, J. et al, 1992). Therefore, the immune status after LDR may be of special significance besides other factors. Further studies are warranted to elucidate the effect of LDR on secretion of cytokines and their role as important links of cellular interactions in the mechanism of LDR-induced stimulation of immunity.

Acknowledgment: This work was supported in part by grants from NSFC.

Table 3 Effect of LDR on the rate of lymphoma induced by split-dose irradiation

Treatment	Number of mice observed	Thymic lymphoma^#
		Number	Percentage
Sham-irradiated control	42	0	0
0.025 Gy x 4	34	0	0
0.075 Gy x 4	33	0	0
1.75 Gy x 4	30	13	43.3
(0.025 Gy-6h-1.75 Gy) x 4	35	8	22.8
(0. 025 Gy-12h-1. 75 Gy) x 4	38	10	26.3
(0.075 Gy-6h-1.75 Gy) x 4	33	5	15.1*
(0.075 Gy-12h-1.75 Gy) x 4	34	6	17.1*

^{#Observed 6 months
after termination of
irradiation; Chi square test: *P<0.05 vs 1.75 Gy x 4 group (Adopted from Li, X.Y.
et al. 1998)}

The Seventh International Conference on Nuclear Engineering
Special Symposium

April 21, 1999
Concorde Ball Room, Keio Plaza inter-Continental Tokyo

RSH > Documents > Tokyo 1999 > Shu-Zheng Liu 1999

For more information please contact the RSH President Jim Muckerheide

For website problems please contact the Webmaster

06/14/06