A wide spectrum of collagen vascular and autoimmune diseases in transgenic rats carrying the env-pX gene of human T lymphocyte virus type I

Yamazaki, Hidetoshi; Ikeda, Hitoshi; Ishizu, Akihiro; Nakamaru, Yuji; Sugaya, Toshiaki; Kikuchi, Kazunori; Yamada, Satoshi; Wakisaka, Akemi; Kasai, Noriyuki; Koike, Takao; Hatanaka, Masakazu; Yoshiki, Takashi

doi:10.1093/intimm/9.2.339

Cited by 47 publications

(47 citation statements)

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“…Additionally, the incidence of arteritis was equivalent to that in untreated env-pX rats (9 of 27, 33%). 18 No evidence of arteritis was found in nine lethally irradiated WKAH rats that received env-pX BMCs.…”

Section: Development Of Necrotizing Arteritis In Lethally Irradiated mentioning

confidence: 93%

“…The env-pX transgene in genomic DNA extracted from the peripheral blood mononuclear cells was amplified by PCR, as described. 18 …”

Section: Polymerase Chain Reaction (Pcr) For the Transgenementioning

confidence: 99%

“…[17][18][19][20][21] In our previous work, the env-pX gene was introduced into the germline of Wistar-King-Aptekman-Hokudai (WKAH) rats under the control of the HTLV-I LTR promoter. 18 The env-pX transgene was expressed constitutively in systemic organs of these rats (env-pX rats). Vasculitis and other collagen vascular diseases occurred in env-pX rats.…”

mentioning

confidence: 99%

“…9 To investigate the pathogenetic role of HTLV-I in these diseases, we established and analyzed rat models for HTLV-I infection 10 -16 and transgenic rat lines carrying the env and/or pX genes of HTLV-I. [17][18][19][20][21] In our previous work, the env-pX gene was introduced into the germline of Wistar-King-Aptekman-Hokudai (WKAH) rats under the control of the HTLV-I LTR promoter. 18 The env-pX transgene was expressed constitutively in systemic organs of these rats (env-pX rats).…”

mentioning

confidence: 99%

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The Role of the Thymus in Development of Necrotizing Arteritis in Transgenic Rats Carrying the env-pX Gene of Human T-Cell Leukemia Virus Type-I

Fugo

Ishizu

Ikeda

et al. 2002

The American Journal of Pathology

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Necrotizing arteritis mimicking polyarteritis nodosa occurred in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I. To investigate the pathogenesis of necrotizing arteritis in these rats (envpX rats), adoptive transfers of spleen cells and bone marrow cells were done from env-pX rats before they developed arteritis to nontransgenic rats. Necrotizing arteritis occurred in lethally irradiated nontransgenic rats reconstituted by env-pX spleen cells, thus indicating that the env-pX transgene in affected vessels may not be essential for the development of arteritis. In contrast, arteritis was not induced in nontransgenic recipients by adoptive transfers of env-pX bone marrow cells, which suggested that T cells derived from the env-pX thymus may play a role in the development of arteritis. To clarify if the process of differentiation of T cells in the env-pX thymus is crucial to develop necrotizing arteritis, reciprocal exchange of thymus frameworks was done between env-pX and nontransgenic rats. Necrotizing arteritis occurred in nontransgenic rats with an env-pX thymus framework, whereas development of arteritis was suppressed in env-pX rats in which the thymus framework was replaced with a nontransgenic one. This collective evidence shows that the thymus is directly associated with the development of necrotizing arteritis in env-pX rats. Human T-cell leukemia virus type-I (HTLV-I) is associated with a number of diseases, including adult T cell leukemia, 1,2 myelopathy, 3,4 uveitis, 5 and probably arthropathy, 6 Sjö gren's syndrome, 7 T cell alveolitis, 7,8 and infective dermatitis. 9 To investigate the pathogenetic role of HTLV-I in these diseases, we established and analyzed rat models for HTLV-I infection 10 -16 and transgenic rat lines carrying the env and/or pX genes of HTLV-I. [17][18][19][20][21] In our previous work, the env-pX gene was introduced into the germline of Wistar-King-Aptekman-Hokudai (WKAH) rats under the control of the HTLV-I LTR promoter. 18 The env-pX transgene was expressed constitutively in systemic organs of these rats (env-pX rats). Vasculitis and other collagen vascular diseases occurred in env-pX rats. Small-to medium-sized arteries in connective tissues around the thymus, salivary glands, testis, pancreas, and in the dermis, but never glomeruli or large vessels such as the aorta, were mainly affected. A cellular infiltrate containing lymphocytes, neutrophils, plasma cells, and histiocytes with proliferation of fibroblastic cells surrounding affected arteries was present, and fibrinoid necrosis was evident in the intima and/or media. These histological characteristics corresponding to necrotizing arteritis and the tissue distribution resemble findings in polyarteritis nodosa in humans. Because autoantibodies, including anti-nuclear and anti-DNA antibodies, were present in the sera, autoimmune phenomena may play a role in the pathogenesis.To determine whether cellular autoimmune responses are involved in the pathogenesis of necrotizing arteritis in env-pX rats...

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Section: Development Of Necrotizing Arteritis In Lethally Irradiated mentioning

confidence: 93%

“…The env-pX transgene in genomic DNA extracted from the peripheral blood mononuclear cells was amplified by PCR, as described. 18 …”

Section: Polymerase Chain Reaction (Pcr) For the Transgenementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The Role of the Thymus in Development of Necrotizing Arteritis in Transgenic Rats Carrying the env-pX Gene of Human T-Cell Leukemia Virus Type-I

Fugo

Ishizu

Ikeda

et al. 2002

The American Journal of Pathology

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“…To investigate the pathogenetic role of the pX gene, we established several transgenic rat models carrying the HTLV-I pX gene under controls of various promoters. [8][9][10] Among them, a transgenic rat carrying the pX gene under control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) type I promoter (lck-pX rat) is a unique rat model for spontaneously occurring epithelial thymomas in the thymic medulla. 10 The endogenous p56lck type I promoter is specifically active in thymic lymphocytes.…”

mentioning

confidence: 99%

Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model

Tsuchikawa

Ikeda

Kikuchi

et al. 2004

Laboratory Investigation

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We earlier reported that Fischer 344/jcl strain (F344) rats carrying a unique pX gene of human T lymphocyte virus type I (HTLV-I) under control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) type I promoter (lck-pX rats) spontaneously developed epithelial thymomas from the thymic medulla. To investigate the role of bone marrow cells carrying the HTLV-I pX gene in development of thymomas, the bone marrow of normal F344 rats after lethal irradiation was reconstituted by bone marrow mononuclear cells (BMMC) of lck-pX rats. Epithelial thymomas similar to the original thymoma of lck-pX rats frequently developed in the nontransgenic recipients within 5 months after the BMMC transplantation. The thymomas expressed the pX gene, thereby indicating the thymoma cells to be of donor BMMC origin. Since the thymoma also developed in nontransgenic recipients reconstituted by BMMC depleted of adherent cells, it is suggested that nonadherent BMMC of donor lck-pX rats may migrate to and lodge in the thymus of recipient nontransgenic rats then transform into thymoma cells with epithelial characteristics. The thymoma cells were shown to bind to Ulex europaeus Agglutinin-1 (UEA-1) lectin, which binds epithelial cells in the thymic medulla. It was also shown that the nonadherent BMMC fraction used for bone marrow reconstitution contained a number of UEA-1-positive cells. Taken together, UEA-1 positive BMMC may be progenitor cells of the epithelial thymoma. The epithelial thymoma in lck-pX rats sheds light on epithelial cell development in thymic medulla and for oncogenesis of epithelial thymoma in humans.

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Chronic graft-versus-host disease-like autoimmune disorders spontaneously occurred in rats with neonatal thymus atrophy

et al. 2005

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We earlier reported that the human T cell leukemia virus type-1 pX gene transduced into rat thymic epithelial cells had an impact on biology of the cells. We report here that FWpX rats born by mating of F344 transgenic rats expressing the pX gene without tissue specificity with nontransgenic Wistar rats developed disorders, including atrophy of the thymus, lymphocytopenia, and inflammatory cell infiltration into multiple organs, similar to events in chronic graft-vs.-host disease (GVHD). Vanishment of thymic epithelial cells especially in the cortex and marked depletion of CD4 CD8 doublepositive thymocytes were evident in the neonatal thymus in these rats. The relative abundance of CD8 compared to CD4 T cells may be related to dominant infiltration of CD8 T cells into the affected organs. Additionally, adoptive transfer of FW-pX splenocytes could induce lymphocytic infiltration into sublethally irradiated wild-type syngeneic recipients. Analysis of the expression level of the Foxp3 gene in peripheral blood mononuclear cells revealed that the numbers of immunoregulatory T cells were less in FW-pX rats than in wild-type rats. The collective evidence suggested that the FWpX rats spontaneously developed chronic GVHD-like autoimmune diseases, following abortive differentiation of T cells in the thymus in early days of the newborn. This rat model may shed light on the pathogenesis of chronic GVHD and also other systemic autoimmune diseases, the etiology of which is unknown.

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A wide spectrum of collagen vascular and autoimmune diseases in transgenic rats carrying the env-pX gene of human T lymphocyte virus type I

Cited by 47 publications

References 3 publications

The Role of the Thymus in Development of Necrotizing Arteritis in Transgenic Rats Carrying the env-pX Gene of Human T-Cell Leukemia Virus Type-I

The Role of the Thymus in Development of Necrotizing Arteritis in Transgenic Rats Carrying the env-pX Gene of Human T-Cell Leukemia Virus Type-I

Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model

Chronic graft-versus-host disease-like autoimmune disorders spontaneously occurred in rats with neonatal thymus atrophy

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