Takahiro Tsuji

A novel animal model of thymic tumour: development of epithelial thymoma in transgenic rats carrying human T lymphocyte virus type I pX gene.

The pX region encodes a major product of human T lymphocyte virus type I (HTLV‐I) that has been implicated previously in tumour formation. To investigate the pathogenesis of pX gene in lymphoid tissues, we established a series of novel transgenic rats carrying the pX gene under the control of a rat lymphocyte‐specific protein tyrosine kinase (p56lck) proximal promoter.

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats

Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.

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

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.

Bone marrow cells carrying the env-pX transgene play a role in the severity but not prolongation of arthritis in human T-cell leukaemia virus type-I transgenic rats: a possible role of articular tissues carrying the transgene in the prolongation of arthritis

Transgenic rats carrying the env‐pX gene of human T‐cell leukaemia virus type‐I (env‐pX rats) were immunized with type II collagen (CII), and chronological alterations of arthritis were compared with findings of collagen‐induced arthritis (CIA) in wildtype Wistar–King–Aptekman–Hokudai (WKAH) rats. Arthritis induced by CII in env‐pX rats was more severe and persisted longer than CIA in WKAH rats. To determine whether the phenomenon is caused mainly by the transgene‐carrying lymphocytes or articular tissues, we immunized lethally irradiated env‐pX and WKAH rats with reciprocal bone marrow cell (BMC) transplantation. A severe but transient arthritis was induced by CII in WKAH rats reconstituted by env‐pX BMC (w/tB/CII rats). On the other hand, in env‐pX rats reconstituted by WKAH BMC, arthritis persisted longer than in w/tB/CII rats, although the degree was less at an early phase after CII immunization. These findings suggest that articular tissues rather than the BMCs carrying the env‐pX transgene play a role in the prolongation of arthritis in env‐pX rats, although BMCs carrying the transgene are associated with the severity of arthritis. When inflammatory cytokines in synovial cells isolated from env‐pX rats before they developed arthritis were examined, interleukin‐6 (IL‐6) was detected at a higher level than in synovial cells from WKAH rats, thus suggesting the critical role of IL‐6 in env‐pX arthritis.

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

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 FW‐pX 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 double‐positive 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 FW‐pX 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.

De novo proliferative glomerulonephritis with monoclonal IgG deposits of the IgG1κ subtype in a kidney allograft.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) has recently been described in cases with glomerular disease. Only 16 cases of recurrent or de novo PGNMID have been reported in the transplanted kidney. Here we report a case of de novo PGNMID in a renal allograft diagnosed in the early stage by protocol biopsy. A 41‐year‐old male with end‐stage kidney disease caused by focal glomerular sclerosis received a living‐related kidney transplant. The post‐transplantation course was stable, except for an early episode of acute T cell‐mediated rejection. Mesangial C1q deposition was found on the 3‐year protocol biopsy. On the 4‐year protocol biopsy, mild mesangioproliferative changes and deposition of IgG, C1q, C3, IgG1, and κ light chain were evident, confirming the diagnosis of PGNMID of the IgG1κ subtype. Furthermore, mild proteinuria was detected at that time. Because a subsequent haematological examination revealed high copy number Epstein–Barr virus (EBV) DNA and free κ light chain in blood, the post‐transplant lymphoproliferative disorder (PTLD) was suspected. Mycophenolate mofetil (MMF) was discontinued and rituximab was administered for the treatment of PTLD; subsequently, the improvement in proteinuria and serum creatinine was found 2 months after rituximab administration.

Microvascular inflammation in early protocol biopsies of renal allografts in cases of chronic active antibody-mediated rejection.

Chronic active antibody‐mediated rejection (chronic ABMR) is one important cause of late‐stage renal allograft loss. However, few reports have used protocol biopsy to observe changes over time in cases that develop chronic ABMR. The aim of this study was to use protocol biopsy to clarify the histological features of cases that develop chronic ABMR.

Decreased expression of thymus-specific proteasome subunit β5t in Down syndrome patients.

The majority of patients with Down syndrome (DS), trisomy 21, have morphologically abnormal thymuses and present with intrinsic immunological abnormalities affecting mainly the cellular immune response. The aim of this study was to examine whether the expression of functionally important molecules is altered in thymic stromal cells in patients with DS.

Difficulty in the clinical diagnosis of epithelioid angiosarcoma

Epithelioid angiosarcoma (EA) is a rare histological variant of angiosarcoma, composed almost exclusively of endothelial cells with an epithelioid morphology [1]. A case of multicentric epithelioid angiosarcoma in a young woman, whose skin lesion was solitary and mimicked a benign subcutaneous nodule, is reported.A 22-year-old woman presented with a 6-month history of induration on the abdomen. A slightly tender, 10-mm-diameter, subcutaneous nodule with a brownish-red skin surface was seen on the [...]