Escolar Documentos
Profissional Documentos
Cultura Documentos
11 of pharmacological
countermeasures for the
acute radiation syndrome
Mark H. Whitnall and Terry C. Pellmar
Armed Forces Radiobiology Research Institute, Uniformed Services University
of the Health Sciences, Bethesda, Maryland
Abstract
Nuclear attacks and acts of radiological terrorism
have emerged as serious security threats. These
developments have increased the need to establish
safe and effective pharmacological countermeasures
that may prevent or ameliorate the effects of ionizing
radiation, to safeguard military personnel, first
responders, and civilians. Requirements include both
radioprotectants (drugs designed to block radiation-
induced damage), radiation mitigators (agents that
ameliorate the initial deleterious molecular events
Correspondence/Reprint request: Dr. Mark H. Whitnall, SRD, AFRRI, 8901 Wisconsin Ave, Bethesda, MD
20889-5603, Maryland. E-mail: whitnall@afrri.usuhs.mil
2 Mark H. Whitnall & Terry C. Pellmar
I. Introduction
Nuclear proliferation, terrorist activity, and the distribution of nuclear and
radioactive materials make incidents involving radiation injuries increasingly
likely. There is a pressing need to develop radiation countermeasures that can
be used in the clinic for small-scale incidents, and outside the clinic in mass
casualty scenarios. This review addresses the status of countermeasures for
ARS, with particular focus on the hematopoietic and GI syndromes that result
from exposure to penetrating ionizing radiation (gamma and neutron). It does
not cover treatments for chronic or late radiation injuries such as lung fibrosis,
kidney dysfunction, or cancer or for internalized radionuclides. Medical
approaches to ARS aim to prevent or ameliorate radiation injury with
radioprotectants or radiation mitigators, or to stimulate recovery of
hematopoiesis or GI regeneration with post-radiation treatments. After decades
of work on radiation countermeasures [1-10], no pharmaceuticals are currently
approved specifically for ARS, although a few agents are approved for
symptoms of clinical radiation exposure. For example, Granulocyte Colony-
Stimulating Factor (G-CSF, or Neupogen®) mitigates radiation-induced
neutropenia. Amifostine is a well characterized radioprotectant that is used to
reduce post-radiation xerostomia in head and neck cancer patients.
Keratinocyte growth factor (KGF, palifermin or Kepivance™) is approved for
mucositis that results from radiation and/or chemotherapy. In the event of a
radiological or nuclear exposure, G-CSF and KGF might be used off-label or
through emergency use authorization but amifostine’s use is limited because of
its toxicity (nausea, vomiting, hypotension) [1].
Drug development is carried out with consideration of the context in which
an agent will be used: small-scale scenarios such as accidents will involve
post-exposure care by nurses and physicians in hospitals, with treatment
guided by some knowledge of the radiation dose received [11]. In those cases,
potential drug side effects may be acceptable, the storage conditions, expense,
administration route and schedule are not limiting factors, and extensive
Radiation countermeasures 3
V. Conclusions
After decades of published work on radiation countermeasures, few drugs
are currently available for countering the effects of external penetrating
ionizing radiation. However, several candidates are emerging that have
significant efficacy in terms of enhancing survival after irradiation, with low
toxicity. No longer purely an academic enterprise, the field is starting to attract
resources from biotechnology companies and funding agencies with a serious
view toward developing products that can be used both within and outside a
hospital setting. Modern biological concepts are being applied to target
specific molecular responses related to direct damage by radiation and
radiation-induced free radicals, initial radiation-triggered events modulating
intracellular and extracellular signaling pathways, and regeneration of
surviving stem and progenitor cells in injured tissue.
References
1. Weiss JF 1997, Environ Health Perspect 105 Suppl. 6, 1473.
2. Neta R. 1998. Radioprotectors. Chemical, Biological and Clinical Perspectives,
E.A. Bump, and K. Malaker, (Eds.), CRC Press, Boca Raton, pp. 237.
3. Maisin JR. 1998. Int J Radiat Biol 73, 443.
4. MacVittie TJ, Farese AM. 2002. The Medical Basis for Radiation-Accident
Preparedness. The Clinical Care of Victims. RC Ricks, ME Berger, FM O'Hara, Jr.
(Eds.). Parthenon Publishing, Boca Raton, pp. 53.
5. Coleman CN, Blakely WF, Fike JR, MacVittie, TJ, Metting NF, Mitchell JB,
Moulder JE, Preston RJ, Seed TM, Stone HB, Tofilon PJ, Wong RS. 2003. Radiat
Res 159, 812.
12 Mark H. Whitnall & Terry C. Pellmar
37. Goel HC, Prakash H, Ali A, Bala M. 2007. Mol Cell Biochem 295, 93.
38. Goel HC, Bala M, Prasad J, Singh S, Agrawala PK, Swahney RC. 2006. J Med
Food 9, 154.
39. Mukherjee PK, Wahile A. 2006. J Ethnopharmacol 103, 25.
40. Held KD, Harrop HA, Michael BD. 1981. Int J Radiat Biol Relat Stud Phys Chem
Med, 40, 613.
41. Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, Hagan MP, Grant
S, Schmidt-Ullrich R. 2003. Radiat Res 159, 283.
42. McBride WH, Chiang CS, Olson JL, Wang CC, Hong JH, Pajonk F, Dougherty
GJ, Iwamoto KS, Pervan M, Liao YP. 2004. Radiat Res 162, 1.
43. Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A. 2006. Circ Res 99, 924.
44. Kirshner J, Jobling MF, Pajares MJ, Ravani SA, Glick AB, Lavin MJ, Koslov S,
Shiloh Y, Barcellos-Hoff MH. 2006. Cancer Res 66, 10861.
45. Woloschak GE, Chang-Liu CM, Jones PS, Jones CA. 1990. Cancer Res 50, 339.
46. Weichselbaum RR, Hallahan DE, Sukhatme V, Dritschilo A, Sherman ML, Kufe
DW. 1991. J Natl Cancer Inst 83, 480.
47. Sherman ML, Datta R, Hallahan DE, Weichselbaum RR, Kufe DW. 1991. J Clin
Invest 87, 1794.
48. Ishihara H, Tsuneoka K, Dimchev AB, Shikita M. 1993. Radiat Res 133, 321.
49. Johnston CJ, Piedboeuf B, Rubin P, Williams JP, Baggs R, Finkelstein JN. 1996.
Radiat Res 145, 762.
50. Chang CM, Elliott TB, Dobson ME, Jackson WE III, Ledney, GD. 2000. J. Radiat
Res (Tokyo) 41, 259.
51. Denham JW, Hauer-Jensen M. 2002. Radiother Oncol 63, 129.
52. Kyrkanides S, Moore AH, Olschowka JA, Daeschner JC, Williams JP, Hansen JT,
Kerry O'Banion M. 2002. Brain Res Mol Brain Res 104, 159.
53. Linard C, Marquette C, Mathieu J, Pennequin A, Clarencon D, Mathe D. 2004. Int
J Radiat Oncol Biol Phys 58, 427.
54. Xiao M, Inal CE, Whitnall MH. 2005. Blood 106, 148b.
55. Bentzen SM. 2006. Nat Rev Cancer 6, 702.
56. Buell MG, Harding RK. 1989. Dig Dis Sci 34, 390.
57. MacNaughton WK, Aurora AR, Bhamra J, Sharkey KA, Miller MJ. 1998. Int J
Radiat Biol 74, 255.
58. Van der Meeren A, Monti P, Lebaron-Jacobs L, Marquette C, Gourmelon P. 2001.
Radiat Res 155, 858.
59. Hauer-Jensen M, Fink LM, Wang J. 2004. Crit Care Med 32, S325.
60. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS,
Chernov MV, Gudkov AV. 1999. Science 285, 1733.
61. Smith WW, Alderman IM, Gillespie RE. 1957. Am J Physiol 191, 124.
62. Peterson VM, Adamovicz JJ, Elliott TB, Moore MM, Madonna GS, Jackson WE
III, Ledney GD, Gause WC. 1994. J Immunol 153, 2321.
63. Patchen ML, MacVittie TJ. 1982. Adv Exp Med Biol 155, 267.
64. Singh VK, Shafran RL, Jackson WE III, Seed TM, Kumar KS. 2006. Exp Mol
Pathol 81, 55.
65. Neta R, Vogel SN, Oppenheim JJ, Douches SD. 1986. Lymphokine Res 5, Suppl.
1, S105.
66. Waddick KG, Song C., Souza L, Uckun FM. 1991. Blood 77, 2364.
14 Mark H. Whitnall & Terry C. Pellmar
67. Monroy RL, Skelly RR, Taylor P, Dubois A, Donahue RE, MacVittie TJ. 1988.
Exp Hematol 16, 344.
68. MacVittie TJ, Farese AM, Jackson W, 3rd. 2005. Health Phys 89, 546.
69. Van Os, R., Lamont, C., Witsell, A., and Mauch, P.M. 1997, Exp Hematol 25, 205.
70. Farese AM, Williams DE, Seiler FR, MacVittie TJ. 1993. Blood 82, 3012.
71. Schuening FG, Appelbaum FR, Deeg HJ, Sullivan-Pepe M, Graham TC, Hackman
R, Zsebo KM, Storb R. 1993. Blood 81, 20.
72. MacVittie TJ, Farese AM, Patchen ML, Myers LA. 1994. Blood 84, 2515.
73. Farese AM, Hunt P, Grab LB, MacVittie TJ. 1996. J Clin Invest 97, 2145.
74. Neelis KJ, Hartong SC, Egeland T, Thomas GR, Eaton DL, Wagemaker G. 1997.
Blood 90, 2565.
75. Drouet M, Mathieu J, Grenier N, Multon E, Sotto JJ, Herodin F. 1999. Stem Cells
17, 273.
76. Duarte RF, Frank DA. 2000. Blood 96, 3422.
77. Farese AM, Casey DB, Smith WG, Vigneulle RM, McKearn JP, MacVittie TJ.
2001. Stem Cells 19, 522.
78. Farese AM, Smith WG, Giri JG, Siegel N, McKearn JP, MacVittie TJ. 2001. Stem
Cells 19, 329.
79. Mouthon MA, Gaugler MH, Van der Meeren A, Vandamme M, Gourmelon P,
Wagemaker G. 2001. Exp Hematol 29, 30.
80. Yang SR, Wen L, Lu YQ, Gong QY, Yu R, Yao MH. 2004. Acta Pharmacol Sin
25, 68.
81. Van der Meeren A, Mouthon MA, Gaugler MH, Vandamme M, Gourmelon P.
2002. Radiat Res 157, 642.
82. Hofer M, Pospisil M, Znojil V, Vacek A, Weiterova L, Hola J, Vacha J. 2002. Eur
J Haematol 68, 4.
83. Hofer M, Weiterova L, Vacek A, Znojil V, Pospisil M, Vacha J. 2003. Eur J
Haematol 71, 204.
84. Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A,
Cordon-Cardo C, Kolesnick R. 2001. Science 293, 293.
85. Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL, Yin S, Hill
DC, Wiemann B, Starnes CO, Havill AM, Lu ZN, Aukerman SL, Pierce GF,
Thomason A, Potten CS, Ulich TR, Lacey DL. 1998. Cancer Res 58, 933.
86. Okunieff P, Li M, Liu W, Sun J, Fenton B, Zhang L, Ding I. 2001. Am J Clin
Oncol 24, 491.
87. Dorr W, Spekl K, Farrell CL. 2002. Cell Prolif 35 Suppl 1, 86.
88. Maclachlan T, Narayanan B, Gerlach VL, Smithson G, Gerwien RW, Folkerts O,
Fey EG, Watkins B, Seed T, Alvarez E. 2005. Int J Radiat Biol 81, 567.
89. Maj JG, Paris F, Haimovitz-Friedman A, Venkatraman E, Kolesnick R, Fuks Z.
2003. Cancer Res 63, 4338.
90. Vial T, Descotes J. 1995. Drug Saf 13, 371.
91. Singh VK, Yadav VS. 2005. Exp Mol Pathol 78, 156.
92. Neelis KJ, Dubbelman YD, Wognum AW, Thomas GR, Eaton DL, Egeland T,
Wagemaker G. 1997. Exp Hematol 25, 1094.
93. BitMansour A, Burns SM, Traver D, Akashi K, Contag CH, Weissman IL, Brown
JM. 2002. Blood 100, 4660.
94. Na Nakorn T, Traver D, Weissman IL, Akashi K. 2002. J Clin Invest 109, 1579.
Radiation countermeasures 15
95. Georges GE, Storb RF. 2002. The Medical Basis for Radiation-Accident
Preparedness. The Clinical Care of Victims. RC Ricks, ME Berger, FM O'Hara Jr
(Eds.). Parthenon Publishing, Boca Raton, pp.73.
96. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez
XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low
WC, Largaespada DA, Verfaillie CM. 2002. Nature 418, 41.
97. Chute JP, Fung J, Muramoto G, Erwin R. 2004. Exp Hematol 32, 308.
98. Changlin Y, Genyao Y. 2005. BJR Suppl 27, 47.
99. Bertho JM, Prat M, Frick J, Demarquay C, Gaugler MH, Dudoignon N, Clairand I,
Chapel A, Gorin NC, Thierry D, Gourmelon P. 2005. Radiat Res 163, 557.
100. Herodin F, Mayol JF, Mourcin F, Drouet M. 2005. Folia Histochem Cytobiol 43,
223.
101. Resnick IB, Slavin S. 2005. BJR Suppl 27, 21.
102. Uozaki H, Fukayama M, Nakagawa K, Ishikawa T, Misawa S, Doi M, Maekawa
K. 2005. BJR Suppl 27, 13.
103. Drouet M, Mourcin F, Grenier N, Delaunay C, Mayol JF, Lataillade JJ, Peinnequin
A, Herodin F. 2005. Bone Marrow Transplant 35, 1201.
104. George RE, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Shamberger RC,
Pulsipher M, Grupp SA, Diller L. 2006. J Clin Oncol 24, 2891.
105. Machtay M, Scherpereel A, Santiago J, Lee J, McDonough J, Kinniry P, Arguiri E,
Shuvaev VV, Sun J, Cengel K, Solomides CC, Christofidou-Solomidou M. 2006.
Radiother Oncol, in press.
106. Southgate TD, Sheard V, Milsom MD, Ward TH, Mairs RJ, Boyd M, Fairbairn LJ.
2006. J Gene Med 8, 557.
107. Niu Y, Shen H, Epperly M, Zhang X, Nie S, Cao S, Greenberger JS. 2005. In Vivo
19, 965.
108. Epperly MW, Defilippi S, Sikora C, Gretton J, Greenberger JS. 2002. Mil Med
167, 71.
109. Carpenter M, Epperly MW, Agarwal A, Nie S, Hricisak L, Niu Y, Greenberger JS.
2005. Gene Ther 12, 685.
110. Kumar KS, Vaishnav YN, Weiss JF. 1988. Pharmacol Ther 39, 301.
111. Doctrow SR, Huffman K, Marcus CB, Tocco G, Malfroy E, Adinolfi CA, Kruk H,
Baker K, Lazarowych N, Mascarenhas J, Malfroy B. 2002. J Med Chem 45, 4549.
112. Langan AR, Khan MA, Yeung IW, Van Dyk J, Hill RP. 2006. Radiother Oncol 79,
231.
113. Martin RF, Broadhurst S, Reum ME, Squire CJ, Clark GR, Lobachevsky PN, White
JM, Clark C, Sy D, Spotheim-Maurizot M, Kelly DP. 2004. Cancer Res 64, 1067.
114. Floersheim GL. 1992. Br J Radiol 65, 1025.
115. Floersheim GL. 1993. Radiat Res 133, 80.
116. Goel HC, Ganguly SK, Prasad J, Jain V. 1996. Indian J Exp Biol 34, 1194.
117. Nunia V, Goyal PK. 2004. J Radiat Res (Tokyo), 45, 11.
118. Nunia V, Sancheti G, Goyal PK. 2006. Br J Radiol, In press.
119. Xu Y, Kiningham KK, Devalaraja MN, Yeh CC, Majima H, Kasarskis EJ, St Clair
DK. 1999. DNA Cell Biol 18, 709.
120. Karin M, Lin A. 2002. Nat Immunol 3, 221.
121. Wang Y, Meng A, Lang H, Brown SA, Konopa JL, Kindy MS, Schmiedt RA,
Thompson JS, Zhou D. 2004. Cancer Res 64, 6240.
16 Mark H. Whitnall & Terry C. Pellmar
122. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira
S, Underhill DM, Aderem A. 2001. Nature 410, 1099.
123. Yu Y, Nagai S, Wu H, Neish AS, Koyasu S, Gewirtz AT. 2006. J Immunol 176, 6194.
124. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD. 2003. J Immunol 170,
5165.
125. Cleveland BioLabs Inc. 2006. http://www.cbiolabs.com/candidates/protectans.
126. Krivokrysenko V. 2006. 9th Annual Force Health Protection Conference.
Albuquerque, New Mexico.
127. Klinman DM. 2004. Expert Opin Biol Ther 4, 937.
128. Takeshita F, Ishii KJ, Ueda A, Ishigatsubo Y, Klinman DM. 2000. Eur J Immunol
30, 108.
129. Srinivasan V, Villa V, Jackson WE III, Klinman DM, Whitnall MH. 2006.
Abstracts, Annual Meeting of the Radiation Research Society.
130. Singh VK, Shafran RL, Jackson WEI, Srinivasan V, Klinman D, Whitnall MH.
2006. Abstracts, Annual Meeting of the Radiation Research Society.
131. Valachovicova T, Slivova V, Sliva D. 2004. Mini-Reviews in Medicinal Chemistry
4, 881.
132. Landauer MR, Srinivasan V, Seed TM. 2003. J Appl Toxicol 23, 379.
133. Davis TA, Clarke TK, Mog SR, Landauer MR. 2006. Int J Radiat Biol, in press.
134. Zhou Y, Mi MT. 2005. J Radiat Res (Tokyo) 46, 425.
135. Liu SS, Chan KY, Leung RC, Law HK, Leung TW, Ngan HY. 2006. Mol Cancer
Ther 5, 1209.
136. Onconova Therapeutics, unpublished data.
137. Perkins MW, Cosenza SC, Ramana Reddy MV, Premkumar Reddy E, Bell S,
Alfieri A, Kumar S. 2006. Abstracts, Annual Meeting of the Radiation Research
Society.
138. Alfieri AA, Liu L, Sharma A, Gorla G, Bell S, Ramana RM, Cosenza S, Reddy PE,
Guha C. 2004. Int J Radiation Oncology Biol Phys 60, Suppl 1, S367.
139. Van der Meeren A, Mouthon MA, Vandamme M, Squiban C, Aigueperse J. 2004.
Radiat Res 161, 549.
140. Shi J, Wang J, Zheng H, Ling W, Joseph J, Li D, Mehta JL, Ponnappan U, Lin P,
Fink LM, Hauer-Jensen M. 2003. Blood Coagul Fibrinolysis 14, 575.
141. Mosnier LO, Griffin JH. 2006. Front Biosci 11, 2381.
142. Masamura K, Oida K, Kanehara H, Suzuki J, Horie S, Ishii H, Miyamori I. 2003.
Arterioscler Thromb Vasc Biol 23, 512.
143. Gaugler MH, Vereycken-Holler V, Squiban C, Vandamme M, Vozenin-Brotons
MC, Benderitter M. 2005. Radiat Res 163, 479.
144. Moulder JE, Fish BL, Cohen EP. 2003. Curr Pharm Des 9, 737.
145. Charrier S, Michaud A, Badaoui S, Giroux S, Ezan E, Sainteny F, Corvol P,
Vainchenker W. 2004. Blood 104, 978.
146. Rodgers KE, Xiong S, diZerega GS. 2002. Cancer Chemother Pharmacol 49, 403.
147. Yoon SC, Park JM, Jang HS, Shinn KS, Bahk YW. 1994. Int J Radiation Oncology
Biol Phys 30, 873.
148. Hosseinimehr SJ., Mahmoudzadeh A, Akhlagpour S. 2006. Cell Biochem Funct, in
press.
149. Pospisil M, Hofer M, Pipalova I, Viklicka S, Netikova J, Sandula J. 1992. Exp
Hematol 20, 891.
Radiation countermeasures 17
150. Juchelkova L, Hofer M, Pospisil M, Pipalova I. 1998. Physiol Res 47, 73.
151. Hofer M, Pospisil M, Znojil V, Hola J, Vacek A, Weiterova L, Streitova D,
Kozubik A. 2006. Radiat Res 166, 556.
152. Whitnall MH, Elliott TB, Harding RA, Inal CE, Landauer MR, Wilhelmsen CL,
McKinney L, Miner VL, Jackson WE 3rd, Loria RM, Ledney GD, Seed TM. 2000.
Int J Immunopharmacol 22, 1.
153. Whitnall MH, Wilhelmsen CL, McKinney L, Miner V, Seed TM, Jackson WE III.
2002. Immunopharmacol Immunotoxicol 24, 595.
154. Whitnall MH, Villa V, Seed TM, Benjack J, Miner V, Lewbart ML, Dowding CA,
Jackson WE III. 2005. Immunopharmacol Immunotoxicol 27, 15.
155. Loria RM. 2002. Steroids 67, 953.
156. Stickney DR, Dowding C, Garsd A, Whitnall MH, Frincke J. 2004. Abstracts,
Annual Meeting of the European Society for Radiation Biology, Budapest, 264.
157. Whitnall MH, Inal CE, Jackson WE III, Miner VL, Villa V, Seed TM. 2001.
Radiat Res 156, 283.
158. Stickney DR, Dowding C, Garsd A, Ahlem C, Whitnall M, McKeon M, Reading
C, Frincke JM. 2006, Int Immunopharmacol 6, 1706.
159. Singh VK, Shafran RL, Inal CE, Jackson WE III, Whitnall MH. 2005.
Immunopharmacol Immunotoxicol 27, 521.
160. Singh VK, Grace MB, Jacobsen KO, Chang C-M, Parekh VI, Inal CE, Shafran RL,
Whitnall AD, Jackson WE III, Whitnall MH. 2006, submitted.
161. Xiao M, Inal CE, Parekh VI, Siddiqi WS, Whitnall MH. 2006. Abstracts, Annual
Meeting of the Radiation Research Society.
162. Jockenhovel F, Vogel E, Reinhardt W, Reinwein D. 1997. Eur J Med Res 2, 293.
163. Gallicchio VS, Chen MG, Watts TD. 1985. Acta Haematol 73, 80.
164. Gallicchio VS, Chen MG, Watts TD. 1984. Int J Cell Cloning 2, 383.
165. Hosseinimehr SJ, Zakaryaee V, Froughizadeh M. 2006. Mol Cell Biochem 287, 193.
166. Herodin F, Drouet M. 2005. Exp Hematol 33, 1071.
167. Kaushansky K. 2001. Ann N Y Acad Sci 938, 131.
168. Inagaki K, Oda T, Naka Y, Shinkai H, Komatsu N, Iwamura H. 2004. Blood 104, 58.
169. Frederickson S, Renshaw MW, Lin B, Smith LM, Calveley P, Springhorn JP,
Johnson K, Wang Y, Su X, Shen Y, Bowdish KS. 2006. Proc Natl Acad Sci USA
103, 14307.
170. Lin X, Takahashi K, Campion SL, Liu Y, Gustavsen GG, Pena LA, Zamora PO.
2006. Int J Mol. Med 17, 833.
171. Bunn HF. 2007. Blood 109, 868.
172. Johnson HM, Ahmed CM. 2006. Cell Mol Biol (Noisy-le-grand) 52, 71.
173. Sato A, Sone S. 2003. Biochem J 371, 603.
174. Rose T, Moreau JL, Eckenberg R, Theze J. 2003. J Biol Chem 278, 22868.
175. Domingues H, Cregut D, Sebald W, Oschkinat H, Serrano L. 1999. Nat Struct Biol
6, 652.
176. Yang Z, Feng J, Li Y, Hu M, Song L, Yu M, Qin W, Shen B. 2005. Mol Immunol
42, 1015.