DOI QR코드

DOI QR Code

Effects of Low-Dose Fractionated Total Body Irradiation on Murine Immune System

마우스에서 전신 저선량 분할 방사선 조사에 의한 면역학적 변화 평가

  • Kim, Mi-Hyoung (Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences) ;
  • Rhu, Sang-Young (Departments of Obstetrics and Gynecology, Korea Cancer Canter Hospital, Korea Institute of Radiological & Medical Sciences) ;
  • Lim, Dae-Seog (Department of Biotechnology, CHA university) ;
  • Song, Jie-Young (Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences)
  • 김미형 (한국원자력의학원 방사선의학연구소 방사선암연구부) ;
  • 유상영 (한국원자력의학원 원자력병원 산부의과) ;
  • 임대석 (차의과학대학교 생명과학대학 바이오공학과) ;
  • 송지영 (한국원자력의학원 방사선의학연구소 방사선암연구부)
  • Received : 2014.07.08
  • Accepted : 2014.08.10
  • Published : 2014.09.30

Abstract

Along with the wide use of radiotherapy in cancer treatment, there is growing interest in beneficial effect of low-dose irradiation (LDI) in cancer therapy. Therefore, we investigate how LDI affects immune responses in mice model. Total body irradiation (TBI) on C57BL/6 mice was given at low-dose rate of $1mGy{\cdot}min^{-1}$ using $^{137}Cs$ source at three times for consecutive three days. Hematological examination, total cell numbers of spleen, populations and characteristics of splenocytes were determined. Total numbers of RBC or platelet in irradiated mice showed no significant changes. WBC counts were decreased in a dose-dependent manner 2 days after TBI, however, these differences are gradually waned until 28 days. Dose-dependent decrease in the number of splenocytes of TBI mice at day 2 was also improved as time progressed. While the level of Foxp3 mRNA was decreased, the frequency of $CD4^+$ T cells and $CD69^+$ cells in spleen was increased at day 2 and 14. Fractionated low-dose TBI on mice exhibited normal body weight with no distinguishable behavior during whole experimental periods. These results suggest that some parameters of immune system could be altered and evaluated by fractionated low-dose TBI and be used to broaden boundary of low dose radiation research.

방사선요법은 항암 치료에서 널리 이용되는 요법으로, 항암치료에 저선량 방사선을 이용하는 것에 대한 관심이 증가되고 있고, 저선량 방사선의 다양한 생물학적 효과가 있음이 보고되고 있다. 그러므로 본 연구에서는 마우스 모델에서 저선량 방사선이 면역반응에 어떠한 영향을 미치는지, 또한 이를 감지할 수 있는지를 조사하였다. C57BL/6 마우스에 $^{137}Cs$ 선원을 이용하여 연속 3일간 총 90 mGy의 저선량 방사선을 전신 조사한 후 마지막 방사선 조사 2, 14, 28일 후에 마우스를 희생시켜 말초 혈액 세포수, 비장 세포수, 비장 내 면역세포의 비율과 활성화 정도를 분석하였다. 말초 혈액 검사를 통해, 저선량 방사선 조사군에서 적혈구와 혈소판 수의 유의적 변화는 관찰할 수 없었으며, 백혈구 수는 마지막 방사선 조사 후 2일째에 선량-의존적인 감소를 보였으나, 점차 회복되는 경향을 나타냈다. 비장세포 수도 2일째 감소를 보였지만 서서히 그 수가 증가됨을 확인하였다. 2일과 14일째에 비장세포의 Foxp3 mRNA가 감소된 반면, CD4 T 세포와 CD69 양성세포가 증가되었다. 마우스에서 분할 저선량 방사선을 전신조사한 결과, 방사선조사군에서 특이적인 임상 증상이나 유의적인 체중감소를 보이지 않았다. 본 연구에서는 마우스를 대상으로 저선량을 분할 조사하였을 경우에도 면역학적 변화를 확인할 수 있으며 이를 통해 향후 저선량 방사선의 생물학적 효과를 뒷받침하는 자료로 활용할 수 있으리라 기대한다.

Keywords

References

  1. Hall EJ, Giaccia AJ. Radiobiology for the Radiobiologist. 5th ed. New York; Lippincott Williams and Wilkins, 2000.
  2. Center for Drug Evaluation and Research (CDER). Guidance for industry, estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, U.S. Department of Health and Human Services, Food and Drug Administration. Pharmacology and Toxicology. 2005.
  3. Williams JP, Brown SL, Georges GE, et al. Animal models for medical countermeasures to radiation exposure. Radiat. Res. 2010;173(4):557-578. https://doi.org/10.1667/RR1880.1
  4. Macklis RM. Radithor and the era of mild radium therapy. JAMA. 1990;264(5):614-618. https://doi.org/10.1001/jama.1990.03450050072031
  5. Sowby FD. International commission on radiological protection: 1978 Stockholm meeting. Radiology. 1978;129(2):533-535. https://doi.org/10.1148/129.2.533
  6. Calabrese EJ. Origin of the linearity no threshold (LNT) dose-response concept. Arch. Toxicol. 2013;87(9):1621-1633. https://doi.org/10.1007/s00204-013-1104-7
  7. Liu SZ, Jin SZ, Liu XD. Radiation-induced bystander effect in immune response. Biomed. Environ. Sci. 2004;17(1):40-46.
  8. Otsuka K, Koana T, Tomita M, et al. Rapid myeloid recovery as a possible mechanism of whole-body radioadaptive response. Radiat. Res. 2008;170(3):307-315. https://doi.org/10.1667/RR1146.1
  9. Liu SZ. Radiation hormesis. A new concept in radiological science. Chin. Med. J. (Engl). 1989;102(10):750-755.
  10. Prekeges JL. Radiation hormesis, or, could all that radiation be good for us? J. Nucl. Med. Technol. 2003;31(1):11-17.
  11. Safwat A. The immunobiology of low-dose total-body irradiation: More questions than answers. Radiat. Res. 2000;153(5 Pt 1):599-604. https://doi.org/10.1667/0033-7587(2000)153[0599:TIOLDT]2.0.CO;2
  12. Tubiana M, Feinendegen LE, Yang C, et al. The linear no-threshold relationship is inconsistent with radiation biologic and experimental data. Radiology. 2009;251(1):13-22. https://doi.org/10.1148/radiol.2511080671
  13. Doss M. Shifting the paradigm in radiation safety. Dose Response. 2012;10(4):562-583. https://doi.org/10.2203/dose-response.11-056.Doss
  14. Doss M. Linear no-threshold model vs. radiation hormesis. Dose Response. 2013;11:480-497. https://doi.org/10.2203/dose-response.13-005.Doss
  15. Morgan WF, Bair WJ. Issues in low dose radiation biology: The controversy continues. A perspective. Radiat. Res. 2013;179(5):501-510. https://doi.org/10.1667/RR3306.1
  16. ICRP. The 2007 recommendations of the international commission on radiological protection. ICRP publication 103. Ann ICRP. 2007;37(2-4):1-332.
  17. Rubner Y, Wunderlich R, Ruhle PF, et al. How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front. Oncol. 2012;2:75.
  18. Farooque A, Mathur R, Verma A, et al. Low-dose radiation therapy of cancer: role of immune enhancement. Expert Rev. Anticanc. 2011;11(5):791-802. https://doi.org/10.1586/era.10.217
  19. Fourquet A, Teillaud JL, Lando D, et al. Effects of low dose total body irradiation (LDTBI) and recombinant human interleukin-2 in mice. Radiother. Oncol. 1993;26(3):219-225. https://doi.org/10.1016/0167-8140(93)90263-8
  20. United Nations. Biological mechanisms of radiation actions at low doses. 1-2. New York. 2012.
  21. Suzuki K and Yamashita S. Low-dose radiation exposure and carcinogenesis. Jpn. J. Clin. Oncol. 2012;42(7):563-568. https://doi.org/10.1093/jjco/hys078
  22. Son YH, Jung DH, Kim SD, et al. Dose and dose rate effects of irradiation on blood count and cytokine level in BALB/c mice. J. Radiation Protection. 2013;38(4):179-184. https://doi.org/10.14407/jrp.2013.38.4.179
  23. Shin SC, Lee KM, Kang YM, et al. Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation. Biochem. Bioph. Res. Co. 2010; 397(4):644-649. https://doi.org/10.1016/j.bbrc.2010.05.121
  24. Gridley DS, Pecaut MJ, Dutta-Roy R, et al. Dose and dose rate effects of whole-body proton irradiation on leukocyte populations and lymphoid organs: part I. Immunol. Lett. 2002;80(1):55-66. https://doi.org/10.1016/S0165-2478(01)00306-6
  25. Pecaut MJ, Gridley DS, Smith AL, et al. Dose and dose rate effects of whole-body proton-irradiation on lymphocyte blastogenesis and hematological variables: part II. Immunol. Lett. 2002;80(1):67-73. https://doi.org/10.1016/S0165-2478(01)00307-8
  26. Ge Q, Hu H, Eisen HN, et al. Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. P. Natl. Acad. Sci. USA. 2002;99(5): 2989-2994. https://doi.org/10.1073/pnas.052714099
  27. Min B, Paul WE. Endogenous proliferation: burst-like CD4 T cell proliferation in lymphopenic settings. Semin. Immunol. 2005;17(3):201-207. https://doi.org/10.1016/j.smim.2005.02.005
  28. Prlic M, Blazar BR, Khoruts A, et al. Homeostatic expansion occurs independently of costimulatory signals. J. Immunol. 2001;167(10):5664-5668. https://doi.org/10.4049/jimmunol.167.10.5664
  29. Maine GN, Mule JJ. Making room for T cells. J. Clin. Invest. 2002;110(2):157-159. https://doi.org/10.1172/JCI0216166
  30. Graca L. New tools to identify regulatory T cells. Eur. J. Immunol. 2005;35:1678-1680. https://doi.org/10.1002/eji.200526303
  31. Ohkura N, Sakaguchi S. Regulatory T cells: roles of T cell receptor for their development and function. Semin. Immunopathol. 2010;32(2):95-106. https://doi.org/10.1007/s00281-010-0200-5
  32. Gridley DS, Rizvi A, Luo-Owen X, et al. Low dose, low dose rate photon radiation modifies leukocyte distribution and gene expression in CD4(+) T cells. J. Radiat. Res. 2009;50(2):139-150. https://doi.org/10.1269/jrr.08095
  33. Bogdandi EN, Balogh A, Felgyinszki N, et al. Effects of low-dose radiation on the immune system of mice after total-body irradiation. Radiat. Res. 2010;174(4):480-489. https://doi.org/10.1667/RR2160.1
  34. Liu R, Xiong S, Zhang L, et al. Enhancement of antitumor immunity by low-dose total body irradiation is associated with selectively decreasing the proportion and number of T regulatory cells. Cell. Mol. Immunol. 2010;7(2):157-162. https://doi.org/10.1038/cmi.2009.117

Cited by

  1. Prediction of Midline Dose from Entrance and Exit Dose Using OSLD Measurements for Total Body Irradiation vol.42, pp.2, 2017, https://doi.org/10.14407/jrpr.2017.42.2.77