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A rat model of HTLV-I infection: development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis

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Abstract

In seropositive HTLV-I carrier rats of the WKAH strain inoculated with 2×107 MT-2 cells at 3–6 months of age, chronic progressive myeloneuropathy, tentatively designated as HTLV-I-associated myelopathy (HAM) rat disease, occurred when the rats were 19–23 months old. Clinical and pathological findings were basically identical to those of seronegative HAM rats of the same strain neonatally inoculated with MT-2 cells. It appears that a high dose of MT-2 cells (108 cells) is more effective for the induction and acceleration of HAM rat disease. Seronegative and seropositive carriers of other strains (F344, ACI, and LEW), WKAH rats inoculated with HUT-78 (a human T cell line without HTLV-I infection), and untreated WKAH rats at comparable ages did not develop HAM rat disease, thereby indicating that development of this disease is caused by HTLV-I infection and is under strict genetic restriction of the host strain. Chronological examination of HAM rat disease induced by 107 MT-2 inoculation into newborn rats showed that the spinal cord lesion began to develop by 12 months of age. T cells were absent in the affected spinal cord throughout the disease process. There was morphological evidence of apoptotic death of oligodendrocytes in the affected spinal cord. Apoptosis was also confirmed by the specific nick end labeling of the nuclear fragmentation in situ, and the apoptotic oligodendrocytes confined to the demyelinating foci, and the number of apoptotic cells positively correlated with severity of the spinal cord lesion. The collective evidence suggests that the major pathogenetic pathway of HAM rat disease appears to be closely related to apoptotic death of the oligodendrocytes, directly or indirectly associated with HTLV-I infection.

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References

  1. Akagi T, Hoshida Y, Yoshino T, Teramoto N, Kondo E, Hayashi K, Takahashi K (1992) Infectivity of human T lymphotropic virus type I to human nervous tissue cells in vitro. Acta Neuropathol 84:147–152

    Google Scholar 

  2. Claphan P, Nagy K, Cheingsong-Popov R, Exley M, Weiss RA (1983) Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science 222:1125–1127

    Google Scholar 

  3. Fan N, Gavalchin J, Paul B, Wells KH, Lane MJ, Poiesz BJ (1992) Infection of peripheral blood mononuclear cells and cell lines by cell-free human T-cell lymphoma/leukemia virus type I. J Clin Microbiol 30:905–910

    Google Scholar 

  4. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    Google Scholar 

  5. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, De Thé G (1985) Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet II: 407–409

    Google Scholar 

  6. Gessain A, Saal F, Gout O, Daniel MT, Flandrin G, De Thé G, Peries J, Sigaux F (1990) High human T-cell lymphotropic virus type I proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese, and African patients with tropical spastic paraparesis. Blood 75:428–433

    Google Scholar 

  7. Gessain A, Louie A, Gout O, Gallo RC, Franchini G (1991) Human T-cell leukemia-lymphoma virus type I (HTLV-I) expression in fresh peripheral blood mononuclear cells from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy. J Virol 65:1628–1633

    Google Scholar 

  8. Hoffman PM, Dhib-Jalbut S, Mikorits JA, Robbins DS, Wolf AL, Bergey GK, Lohrey NC, Weislow OS, Ruscetti FW (1992) Human T-cell leukemia virus type I infection of monocytes and microglial cells in primary human cultures. Proc Natl Acad Sci USA 89:11 784–11 788

    Google Scholar 

  9. Hoshino H, Tanaka H, Shimotohno K, Miwa M, Nagai M, Shimoyama M, Sugimura T (1984) Immortalization of peripheral blood lymphocytes of cats by human T-cell leukemia virus. Int J Cancer 34:513–517

    Google Scholar 

  10. Hoxie JA, Matthews DM, Cines DB (1984) Infection of human endothelial cells by human T-cell leukemia virus type I. Proc Natl Acad Sci USA 81:7591–7595

    Google Scholar 

  11. Ishiguro N, Abe M, Seto K, Sakurai H, Ikeda H, Wakisaka A, Togashi T, Tateno M, Yoshiki T (1992) 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 176:981–989

    Google Scholar 

  12. Itoyama Y, Minato S, Kira J, Goto I, Sato H, Okochi K, Yamamoto N (1988) Spontaneous proliferation of peripheral blood lymphocytes increased inpatients with HTLV-I associated myelopathy. Neurology 38:1302–1307

    Google Scholar 

  13. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S (1990) Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurolgical disease. Nature 348:245–248

    Google Scholar 

  14. Kannagi M, Harada S, Maruyama I, Inoko H, Igarashi H, Kuwashima G, Sato S, Morita M, Kidokoro M, Sugimoto M, Funahashi S, Osame M, Shida H (1991) Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene product by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. Int Immunol 3:761–767

    Google Scholar 

  15. Kitajima I, Yamamoto K, Sato K, Nakajima Y, Nakajima T, Maruyama I, Osame M, Nishioka K (1991) Detection of human T cell lymphotropic virus type I proviral DNA and its gene expression in synovial cells in chronic inflammatory arthropathy. J Clin Invest 88:1315–1322

    Google Scholar 

  16. Koenig S, Woods RM, Brewah YA, Newell AJ, Jones GM, Boone E, Adelsberger JW, Baseler MW, Robinson SM, Jacobson S (1993) Characterization of MHC class I restricted cytotoxic T cell responses to Tax in HTLV-I infected patients with neurologic disease. J Immunol 151:3874–3883

    Google Scholar 

  17. Kushida S, Matsumura M, Tanaka H, Ami Y, Hori M, Kobayashi M, Uchida K, Yagami K, Kameyama T, Yoshizawa T, Mizusawa H, Iwasaki Y, Miwa M (1993) HTLV-I-associated myelopathy/tropical spastic paraparesis-like rats by intravenous injection of HTLV-I-producing rabbit or human T-cell line into adult WKA rats. Jpn J Cancer Res 84:831–833

    Google Scholar 

  18. Louis J-C, Magal E, Takayama S, Varon S (1993) CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689–692

    Google Scholar 

  19. Markham PD, Salahuddin SZ, Macchi B, Robert-Guroff M, Gallo RC (1984) Transformation of differnt phenotypic types of human bone marrow T-lymphocytes by HTLV-I. Int J Cancer 33:13–17

    Google Scholar 

  20. Maruyama I, Tihara J, Sakashita I, Mizoguti R, Mori S, Usuku K, Jonosono M, Tara M, Matsumoto M, Niina S, Sonoda S, Yasaki S, Osame M (1988) HTLV-I associated bronchopneumonopathy — A new clinical entity? Am Rev Res Dis 137:46

    Google Scholar 

  21. Matsuura A, Ishii Y, Yuasa H, Narita H, Kon S, Takami T, Kikuchi K (1984) Rat T lymphocyte antigens comparable with mouse Lyt-1 and Lyt-2, 3 antigenic systems: characterization by monoclonal antibodies. J Immunol 132:316–322

    Google Scholar 

  22. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K, Hinuma Y (1981) Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukemic T-cells. Nature 294:770–771

    Google Scholar 

  23. Miyoshi I, Taguchi H, Fujishita M, Yoshimoto S, Kubonishi I, Ohtsuki Y, Shiraishi Y, Akagi T (1983) Transformation of monkey lymphocytes with adult T-cell leukaemia virus. Lancet I:1016

    Google Scholar 

  24. Miyoshi I, Yoshimoto S, Taguchi H, Kubonishi I, Fujishita M, Ohtsuki Y, Shiraishi Y, Akagi T (1983) Transformation of rabbit lymphocytes with adult T-cell leukemia virus. Jpn J Cancer Res 74:1–4

    Google Scholar 

  25. Mochizuki M, Watanabe T, Yamaguchi K, Takatsuki K, Yoshimura K, Shirao M, Nakashima S, Mori S, Araki S, Miyata N (1992) HTLV-I uveitis: a distinct clinical entity caused by HTLV-I. Jpn J Cancer Res 83:236–239

    Google Scholar 

  26. Nishioka K, Maruyama J, Sato K, Kitajima I, Nakajima Y, Osame M (1989) Chronic inflammatory arthropathy associated with HTLV-I. Lancet I:441

    Google Scholar 

  27. Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M (1986) HTLV-I associated myelopathy, a new clinical entity. Lancet I:1031–1032

    Google Scholar 

  28. Osame M, Matsumoto M, Usuku K, Izumo S, Ijichi N, Amitani H, Tara M, Igata A (1987) Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia like cells. Ann Neurol 21:117–122

    Google Scholar 

  29. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) Detection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419

    Google Scholar 

  30. Selmaj KW, Raine CS (1988) Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23:339–346

    Google Scholar 

  31. Selmaj KW, Raine CS, Farooq M, Norton WT, Brosman CF (1991) Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol 147:1522–1529

    Google Scholar 

  32. Tateno M, Kondo N, Itoh T, Chubachi T, Togashi T, Yoshiki T (1984) Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization. J Exp Med 159:1105–1116

    Google Scholar 

  33. Tendler CL, Greenberg SJ, Burton JD, Danielpour D, Kim S-J, Blattner WA, Manns A, Waldmann TA (1991) Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. J Cell Biochem 46:302–311

    Google Scholar 

  34. Vernant JC, Maurs L, Gessain A, Barin F, Gout O, Delaporte JM, Sanhadji K, Buisson G, De Thé G (1987) Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases. Ann Neurol 21:123–130

    Google Scholar 

  35. Vernant JC, Buisson G, Magdelaine J, DeThore J, Jouannelle A, Neisson-Vernant C, Monplaisir N (1988) T-lymphocyte alveolitis, tropical spastic paresis, and Sjögren syndrome. Lancet I:177

    Google Scholar 

  36. Watabe K, Saida T, Kim SU (1989) Human and simian glial cells infected by human T-lymphotropic virus type I in culture. J Neuropathol Exp Neurol 48:610–619

    Google Scholar 

  37. Williams GT, Smith CA (1993) Molecular regulation of apoptosis: genetic controls on cell death. Cell 74:777–779

    Google Scholar 

  38. Yamaki T, Uede T, Sugawara Y, Wada T, Yamaguchi A, Kokai Y, Kikuchi K (1987) Characterization of rat T cell subset antigen by monoclonal antibody. Microbiol Immunol 31: 793–807

    Google Scholar 

  39. Yoshida M, Miyoshi I, Hinuma Y (1982) Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 79:2031–2035

    Google Scholar 

  40. Yoshida M, Osame M, Kawai H, Toita M, Kuwasaki N, Nishida Y, Hiraki Y, Takahashi K, Nomura K, Sonoda S, Eiraku N, Ijichi S, Usuku K (1989) Increased replication of HTLV-I in HTLV-I-associated myelopathy. Ann Neurol 26:331–335

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Hokkaido University School of Medicine Kita-15, Nishi-7, Kita-ku, 060, Sapporo, Japan

    K. Seto, M. Abe, O. Ohya, O. Itakura, N. Ishiguro, H. Ikeda, A. Wakisaka & T. Yoshiki

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  1. K. Seto
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  2. M. Abe
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  3. O. Ohya
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  7. A. Wakisaka
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  8. T. Yoshiki
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Seto, K., Abe, M., Ohya, O. et al. A rat model of HTLV-I infection: development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis. Acta Neuropathol 89, 483–490 (1995). https://doi.org/10.1007/BF00571502

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  • DOI: https://doi.org/10.1007/BF00571502

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