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. 1994 Nov;68(11):7221–7226. doi: 10.1128/jvi.68.11.7221-7226.1994

High incidence of HAM/TSP-like symptoms in WKA rats after administration of human T-cell leukemia virus type 1-producing cells.

S Kushida 1, H Mizusawa 1, M Matsumura 1, H Tanaka 1, Y Ami 1, M Hori 1, K Yagami 1, T Kameyama 1, Y Tanaka 1, A Yoshida 1, et al.
PMCID: PMC237161  PMID: 7933104

Abstract

We demonstrate a significantly high incidence of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)-or tropical spastic paraparesis (TSP)-like symptoms in WKA rats after injection with HTLV-1-producing MT-2 cells, while no symptoms were observed in F344 rats injected with MT-2 cells or in control WKA rats. Five of the eight (63%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 105 weeks of age, but none of seven MT-2-injected F344 rats or eight control WKA rats showed symptoms. This high incidence of HAM/TSP-like symptoms in WKA rats was statistically significant (P < 0.05). Six of the eight (75%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 108 weeks of age. HAM/TSP-like symptoms were also observed in one of the two WKA rats injected with HTLV-1-producing Ra-1 cells at 128 weeks of age. HTLV-1 provirus was detected in peripheral blood mononuclear cells in both WKA and F344 rats. The provirus was detected in the spinal cords of the HAM/TSP-like WKA rats that had severe neuropathological changes. WKA and F344 rats showed no significant difference in antibody response against HTLV-1 Gag antigen. However, the antibody response against the C-terminal half of gp46 HTLV-1 envelope protein was lower in WKA rats than in F344 rats. Pathological analysis of the HAM/TSP-like rats showed degeneration of the white matter of the spinal cord and peripheral nerves. These findings suggest that both the genetic background of the host and HTLV-1 infection are important in neuropathogenesis of HAM/TSP-like paraparesis in rats.

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  1. Albrecht H., Shakhov A. N., Jongeneel C. V. trans activation of the tumor necrosis factor alpha promoter by the human T-cell leukemia virus type I Tax1 protein. J Virol. 1992 Oct;66(10):6191–6193. doi: 10.1128/jvi.66.10.6191-6193.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albretsen C., Haukanes B. I., Aasland R., Kleppe K. Optimal conditions for hybridization with oligonucleotides: a study with myc-oncogene DNA probes. Anal Biochem. 1988 Apr;170(1):193–202. doi: 10.1016/0003-2697(88)90108-x. [DOI] [PubMed] [Google Scholar]
  3. Ami Y., Kushida S., Matsumura M., Yoshida Y., Kameyama T., Sugiyama Y., Yagami K., Uchida M., Uchida K., Koiso K. Vertical transmission of HTLV-1 in HTLV-1 carrier rat. Jpn J Cancer Res. 1992 Dec;83(12):1241–1243. doi: 10.1111/j.1349-7006.1992.tb02751.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bartholomew C., Cleghorn F., Charles W., Ratan P., Roberts L., Maharaj K., Jankey N., Daisley H., Hanchard B., Blattner W. HTLV-I and tropical spastic paraparesis. Lancet. 1986 Jul 12;2(8498):99–100. doi: 10.1016/s0140-6736(86)91626-0. [DOI] [PubMed] [Google Scholar]
  5. Bhigjee A. I., Bill P. L., Wiley C. A., Windsor I. M., Matthias D. A., Amenomori T., Wachsman W., Moorhouse D. Peripheral nerve lesions in HTLV-I associated myelopathy (HAM/TSP). Muscle Nerve. 1993 Jan;16(1):21–26. doi: 10.1002/mus.880160106. [DOI] [PubMed] [Google Scholar]
  6. Bhigjee A. I., Wiley C. A., Wachsman W., Amenomori T., Pirie D., Bill P. L., Windsor I. HTLV-I-associated myelopathy: clinicopathologic correlation with localization of provirus to spinal cord. Neurology. 1991 Dec;41(12):1990–1992. doi: 10.1212/wnl.41.12.1990. [DOI] [PubMed] [Google Scholar]
  7. Budka H. Human immunodeficiency virus (HIV)-induced disease of the central nervous system: pathology and implications for pathogenesis. Acta Neuropathol. 1989;77(3):225–236. doi: 10.1007/BF00687573. [DOI] [PubMed] [Google Scholar]
  8. Burnette W. N. "Western blotting": electrophoretic transfer of proteins from sodium dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem. 1981 Apr;112(2):195–203. doi: 10.1016/0003-2697(81)90281-5. [DOI] [PubMed] [Google Scholar]
  9. Chad D. A., Recht L. D. Neuromuscular complications of systemic cancer. Neurol Clin. 1991 Nov;9(4):901–918. [PubMed] [Google Scholar]
  10. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  11. Fontana A., Fierz W., Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature. 1984 Jan 19;307(5948):273–276. doi: 10.1038/307273a0. [DOI] [PubMed] [Google Scholar]
  12. Furukawa Y., Fujisawa J., Osame M., Toita M., Sonoda S., Kubota R., Ijichi S., Yoshida M. Frequent clonal proliferation of human T-cell leukemia virus type 1 (HTLV-1)-infected T cells in HTLV-1-associated myelopathy (HAM-TSP). Blood. 1992 Aug 15;80(4):1012–1016. [PubMed] [Google Scholar]
  13. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  14. Gill T. J., 3rd, Kunz H. W., Misra D. N., Hassett A. L. The major histocompatibility complex of the rat. Transplantation. 1987 Jun;43(6):773–785. [PubMed] [Google Scholar]
  15. Ijichi S., Eiraku N., Osame M., Izumo S., Kubota R., Maruyama I., Matsumoto M., Sonoda S. In vitro modulation of lymphocyte proliferation by prednisolone and interferon-alpha in patients with HTLV-I-associated myelopathy (HAM). J Neuroimmunol. 1989 Jul;23(2):175–178. doi: 10.1016/0165-5728(89)90037-4. [DOI] [PubMed] [Google Scholar]
  16. Ikeda M., Fujino R., Matsui T., Yoshida T., Komoda H., Imai J. A new agglutination test for serum antibodies to adult T-cell leukemia virus. Gan. 1984 Oct;75(10):845–848. [PubMed] [Google Scholar]
  17. Ishiguro N., Abe M., Seto K., Sakurai H., Ikeda H., Wakisaka A., Togashi T., Tateno M., Yoshiki T. A rat model of human T lymphocyte virus type I (HTLV-I) infection. 1. Humoral antibody response, provirus integration, and HTLV-I-associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats. J Exp Med. 1992 Oct 1;176(4):981–989. doi: 10.1084/jem.176.4.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Itoyama Y., Kira J., Fujii N., Goto I., Yamamoto N. Increases in helper inducer T cells and activated T cells in HTLV-I-associated myelopathy. Ann Neurol. 1989 Aug;26(2):257–262. doi: 10.1002/ana.410260212. [DOI] [PubMed] [Google Scholar]
  19. Itoyama Y., Minato S., Goto I., Okochi K., Yamamoto N. Elevated serum antibody titers to Epstein-Barr virus in HTLV-I-associated myelopathy (HAM). Neurology. 1988 Oct;38(10):1650–1653. doi: 10.1212/wnl.38.10.1650. [DOI] [PubMed] [Google Scholar]
  20. Iwasaki Y. Pathology of chronic myelopathy associated with HTLV-I infection (HAM/TSP). J Neurol Sci. 1990 Apr;96(1):103–123. doi: 10.1016/0022-510x(90)90060-z. [DOI] [PubMed] [Google Scholar]
  21. Jacobson S., Gupta A., Mattson D., Mingioli E., McFarlin D. E. Immunological studies in tropical spastic paraparesis. Ann Neurol. 1990 Feb;27(2):149–156. doi: 10.1002/ana.410270209. [DOI] [PubMed] [Google Scholar]
  22. Jacobson S., Shida H., McFarlin D. E., Fauci A. S., Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990 Nov 15;348(6298):245–248. doi: 10.1038/348245a0. [DOI] [PubMed] [Google Scholar]
  23. Kay D. G., Gravel C., Pothier F., Laperrière A., Robitaille Y., Jolicoeur P. Neurological disease induced in transgenic mice expressing the env gene of the Cas-Br-E murine retrovirus. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4538–4542. doi: 10.1073/pnas.90.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kira J., Itoyama Y., Koyanagi Y., Tateishi J., Kishikawa M., Akizuki S., Kobayashi I., Toki N., Sueishi K., Sato H. Presence of HTLV-I proviral DNA in central nervous system of patients with HTLV-I-associated myelopathy. Ann Neurol. 1992 Jan;31(1):39–45. doi: 10.1002/ana.410310108. [DOI] [PubMed] [Google Scholar]
  25. Kira J., Koyanagi Y., Yamada T., Itoyama Y., Goto I., Yamamoto N., Sasaki H., Sakaki Y. Increased HTLV-I proviral DNA in HTLV-I-associated myelopathy: a quantitative polymerase chain reaction study. Ann Neurol. 1991 Feb;29(2):194–201. doi: 10.1002/ana.410290214. [DOI] [PubMed] [Google Scholar]
  26. Kushida S., Matsumura M., Tanaka H., Ami Y., Hori M., Kobayashi M., Uchida K., Yagami K., Kameyama T., Yoshizawa T. HTLV-1-associated myelopathy/tropical spastic paraparesis-like rats by intravenous injection of HTLV-1-producing rabbit or human T-cell line into adult WKA rats. Jpn J Cancer Res. 1993 Aug;84(8):831–833. doi: 10.1111/j.1349-7006.1993.tb02052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miyoshi I., Kubonishi I., Yoshimoto S., Shiraishi Y. A T-cell line derived from normal human cord leukocytes by co-culturing with human leukemic T-cells. Gan. 1981 Dec;72(6):978–981. [PubMed] [Google Scholar]
  28. Miyoshi I., Yoshimoto S., Taguchi H., Kubonishi I., Fujishita M., Ohtsuki Y., Shiraishi Y., Akagi T. Transformation of rabbit lymphocytes with T-cell leukemia virus. Gan. 1983 Feb;74(1):1–4. [PubMed] [Google Scholar]
  29. Moore G. R., Traugott U., Scheinberg L. C., Raine C. S. Tropical spastic paraparesis: a model of virus-induced, cytotoxic T-cell-mediated demyelination? Ann Neurol. 1989 Oct;26(4):523–530. doi: 10.1002/ana.410260405. [DOI] [PubMed] [Google Scholar]
  30. Mori M., Kinoshita K., Ban N., Yamada Y., Shiku H. Activated T-lymphocytes with polyclonal gammopathy in patients with human T-lymphotropic virus type I--associated myelopathy. Ann Neurol. 1988 Aug;24(2):280–282. doi: 10.1002/ana.410240220. [DOI] [PubMed] [Google Scholar]
  31. Nyunoya H., Ogura T., Kikuchi M., Iwamoto H., Yamashita K., Maekawa M., Takebe Y., Miyamura K., Yamazaki S., Shimotohno K. Expression of HTLV-I envelope protein fused to hydrophobic amino-terminal peptide of baculovirus polyhedrin in insect cells and its application for serological assays. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1311–1321. doi: 10.1089/aid.1990.6.1311. [DOI] [PubMed] [Google Scholar]
  32. Osame M., Matsumoto M., Usuku K., Izumo S., Ijichi N., Amitani H., Tara M., Igata A. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells. Ann Neurol. 1987 Feb;21(2):117–122. doi: 10.1002/ana.410210203. [DOI] [PubMed] [Google Scholar]
  33. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  34. Palker T. J., Riggs E. R., Spragion D. E., Muir A. J., Scearce R. M., Randall R. R., McAdams M. W., McKnight A., Clapham P. R., Weiss R. A. Mapping of homologous, amino-terminal neutralizing regions of human T-cell lymphotropic virus type I and II gp46 envelope glycoproteins. J Virol. 1992 Oct;66(10):5879–5889. doi: 10.1128/jvi.66.10.5879-5889.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  36. Robbins D. S., Shirazi Y., Drysdale B. E., Lieberman A., Shin H. S., Shin M. L. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol. 1987 Oct 15;139(8):2593–2597. [PubMed] [Google Scholar]
  37. Rodgers-Johnson P., Gajdusek D. C., Morgan O. S., Zaninovic V., Sarin P. S., Graham D. S. HTLV-I and HTLV-III antibodies and tropical spastic paraparesis. Lancet. 1985 Nov 30;2(8466):1247–1248. doi: 10.1016/s0140-6736(85)90778-0. [DOI] [PubMed] [Google Scholar]
  38. Said G., Goulon-Goeau C., Lacroix C., Fève A., Descamps H., Fouchard M. Inflammatory lesions of peripheral nerve in a patient with human T-lymphotropic virus type I--associated myelopathy. Ann Neurol. 1988 Aug;24(2):275–277. doi: 10.1002/ana.410240218. [DOI] [PubMed] [Google Scholar]
  39. Selmaj K., Raine C. S., Farooq M., Norton W. T., Brosnan C. F. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol. 1991 Sep 1;147(5):1522–1529. [PubMed] [Google Scholar]
  40. Shinzato O., Kamihira S., Ikeda S., Kondo H., Kanda T., Nagata Y., Nakayama E., Shiku H. Relationship between the anti-HTLV-1 antibody level, the number of abnormal lymphocytes and the viral-genome dose in HTLV-1-infected individuals. Int J Cancer. 1993 May 8;54(2):208–212. doi: 10.1002/ijc.2910540208. [DOI] [PubMed] [Google Scholar]
  41. Suga T., Kameyama T., Kinoshita T., Shimotohno K., Matsumura M., Tanaka H., Kushida S., Ami Y., Uchida M., Uchida K. Infection of rats with HTLV-1: a small-animal model for HTLV-1 carriers. Int J Cancer. 1991 Nov 11;49(5):764–769. doi: 10.1002/ijc.2910490522. [DOI] [PubMed] [Google Scholar]
  42. Tanaka Y., Yasumoto M., Nyunoya H., Ogura T., Kikuchi M., Shimotohno K., Shiraki H., Kuroda N., Shida H., Tozawa H. Generation and characterization of monoclonal antibodies against multiple epitopes on the C-terminal half of envelope gp46 of human T-cell leukemia virus type-I (HTLV-I). Int J Cancer. 1990 Oct 15;46(4):675–681. doi: 10.1002/ijc.2910460421. [DOI] [PubMed] [Google Scholar]
  43. Tanaka Y., Zeng L., Shiraki H., Shida H., Tozawa H. Identification of a neutralization epitope on the envelope gp46 antigen of human T cell leukemia virus type I and induction of neutralizing antibody by peptide immunization. J Immunol. 1991 Jul 1;147(1):354–360. [PubMed] [Google Scholar]
  44. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Vernant J. C., Maurs L., Gessain A., Barin F., Gout O., Delaporte J. M., Sanhadji K., Buisson G., de-Thé G. Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases. Ann Neurol. 1987 Feb;21(2):123–130. doi: 10.1002/ana.410210204. [DOI] [PubMed] [Google Scholar]

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