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2.
Am J Transplant ; 15(10): 2565-75, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26012352

RESUMO

Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-γ. In addition, T-5224 blocked the nuclear translocation of c-Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT.


Assuntos
Benzofenonas/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante das Ilhotas Pancreáticas/imunologia , Isoxazóis/uso terapêutico , Animais , Benzofenonas/farmacologia , Rejeição de Enxerto/imunologia , Imunossupressores/farmacologia , Isoxazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Transcrição AP-1/antagonistas & inibidores , Transplante Homólogo
4.
Am J Surg Pathol ; 25(7): 918-24, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11420463

RESUMO

Adult neuroblastoma (ANB) is a rare and poorly recognized entity among a histologically defined group of small, round-cell tumors arising in the retroperitoneum and abdomen. Eight cases of ANB were compared with seven cases of primitive neuroectodermal tumor (PNET) in these locations to identify clinicopathologic features that could be used to distinguish between the two lesions. The ANB study group included four men and four women 22-74 years of age (mean 38 years). Five patients with ANB presented with inflammatory symptoms or elevated levels of catecholamines and their metabolites. Five of the ANB tumors were classified as undifferentiated and three as poorly differentiated with a background of neuropil. These cases often showed immunoreactivity for multiple neural markers such as CD56, chromogranin A, synaptophysin, neurofilament, and neuron-specific enolase, but were negative for CD99, cytokeratins, desmin, myogenin, smooth muscle actin, muscle-specific actin, CD34, S-100 protein, and CD45. In contrast, all of the PNETs were positive for CD99, and four (57%) were also positive for cytokeratins. Two cases of ANB of the undifferentiated subtype had ultrastructural features characteristic of neuroblastoma and lacked a chimeric transcript (EWS-FLI1or ERG), which is specific for PNET. All five patients with the undifferentiated subtype of ANB and six of the seven patients with PNET died of their disease within 3 years of discovery of the lesion. Our results show that ANB, although rare, should be considered in the differential diagnosis of patients with small, round-cell tumors in the retroperitoneum and abdomen. Appropriate immunohistochemical studies and laboratory examination enable pathologists to distinguish ANB from other differential diagnoses, especially PNET.


Assuntos
Neoplasias Abdominais/patologia , Neuroblastoma/patologia , Neoplasias Retroperitoneais/patologia , Neoplasias Abdominais/metabolismo , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumores Neuroectodérmicos Primitivos/patologia , Neoplasias Retroperitoneais/metabolismo
5.
J Gastroenterol ; 36(12): 842-7, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11777213

RESUMO

We report a patient with combined hepatocellular carcinoma and cholangiocarcinoma (HCC-CC) growing into the common bile duct (CBD) and showing obstructive jaundice within 2 years of the onset of the disease. The patient was a 59-year-old Japanese man in whom, at the age of 57 years. a hepatic tumor was discovered by diagnostic imaging during follow-up of hepatitis B surface antigen (HBsAg)-positive liver cirrhosis. The tumor was diagnosed as HCC. Epirubicin was injected twice, intraarterially. The patient then received oral etoposide therapy for the next 14 months. The treatment was initially effective, but approximately 2 years after the hepatic tumor was discovered, local recurrence of the tumor and a tumor thrombus in the CBD were discovered. Although he was treated with percutaneous transhepatic biliary drainage (PTBD), to reduce obstructive jaundice, the jaundice was irreversible and he died of severe hepatic failure. The autopsy findings confirmed that the hepatic tumor was HCC-CC, in which the HCC and CC components expressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9), respectively, which accurately reflected the disease process. The underlying mechanism of the growth of HCC-CC into the CBD may differ from the underlying mechanism of the development of icteric-type HCC.


Assuntos
Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Hepáticas/patologia , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/terapia , Neoplasias do Ducto Colédoco/diagnóstico por imagem , Neoplasias do Ducto Colédoco/terapia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Radiografia
6.
APMIS ; 108(6): 459-66, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11028810

RESUMO

To investigate the pathogenetic role of human T-lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, was examined with regard to chronological neuropathology, from early asymptomatic phase to late disease. In the thoracic spinal cord of rats with HTLV-I infection, the first event was the appearance of apoptosis of oligodendrocytes beginning at 7 months after induced infection, thereafter followed by the appearance of white matter degeneration, increase of macrophages/activated microglia and of gemistocytic astrocytes at 12, 15 and 20 months, respectively. In the spinal cord, HTLV-I provirus DNA was evident as early as 4 months after the infection, and HTLV-I pX and the tumor necrosis factor (TNF)-alpha messages began to be expressed at age 7 months, just before or at the same time as the appearance of apoptotic cells. Collective evidence suggests that the apoptotic death of oligodendrocytes, which may be induced either directly by the local expression of HTLV-I or indirectly by TNF-alpha, through the transactive function of p40Tax, is the major cause of chronic progressive myeloneuropathy in Wistar-King-Aptekman-Hokudai rats with HTLV-I infection.


Assuntos
Apoptose , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Oligodendroglia/patologia , Paraparesia Espástica Tropical/patologia , Medula Espinal/patologia , Envelhecimento , Animais , Portador Sadio , Linhagem Celular , Fragmentação do DNA , DNA Viral/isolamento & purificação , Proteína Glial Fibrilar Ácida/análise , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Oligodendroglia/virologia , Paraparesia Espástica Tropical/fisiopatologia , Reação em Cadeia da Polimerase , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/virologia , Fatores de Tempo
7.
Jpn J Clin Oncol ; 30(7): 313-7, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11007165

RESUMO

We present a rare case of primary extracranial meningioma in a 36-year-old man, who had a solitary multinodular mass located in the plantar muscle of the foot. The histology of specimens from simple excision was typical of meningioma, showing bland spindle cell proliferation with a whorl pattern. Immunohistochemical analysis demonstrated that the tumor cells showed diffuse and strong positivity for epithelial membrane antigen as well as moderate reactivity for cytokeratin and vimentin. Ultrastructurally, the tumor cells were characterized by thin bipolar cytoplasmic processes and joined by multiple small desmosomes. There were frequent pinocytotic vesicles and a distinct external lamina on the cell surface. These findings suggest that this primary ectopic meningioma, arising in the soft tissue, may have been derived from perineurial cells of the peripheral nerve, but was morphologically distinguishable from perineurioma. Primary extracranial meningioma should be included in the differential diagnosis of soft-tissue spindle cell tumors, especially those of peripheral nerve origin.


Assuntos
Doenças do Pé/patologia , Meningioma/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Queratinas/análise , Masculino , Meningioma/ultraestrutura , Neoplasias de Bainha Neural/patologia , Neoplasias de Tecidos Moles/ultraestrutura , Vimentina/análise
8.
J Neuroimmunol ; 106(1-2): 105-13, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10814788

RESUMO

We reported that the tumor necrosis factor-alpha (TNF-alpha) expression and apoptotic death of oligodendrocytes appeared to be a major pathogenesis of the demyelination of spinal cords of Wistar-King-Aptekman-Hokudai (WKAH) rats with human T lymphocyte virus type I (HTLV-I) infection, HAM rats. In the present study, we examined the sensitivity to TNF-alpha-induced cell death of in vitro-separated oligodendrocytes from HTLV-I-infected WKAH rats. Although the number of non-viable oligodendrocytes increased by adding recombinant TNF-alpha, in a dose-dependent manner, in both HTLV-I-infected and uninfected control rats, oligodendrocytes from the infected rats were more susceptible to TNF-alpha. In situ detection of DNA fragmentation showed apoptotic death of oligodendrocytes. The expression of bcl-2, an anti-apoptotic gene, was strongly down-regulated in oligodendrocytes of the infected rats but not in the control rats. We suggest that the down-regulation of bcl-2 expression in the oligodendrocytes of the HTLV-I-infected rats may increase the susceptibility to TNF-alpha-induced apoptosis of oligodendrocytes, the result being development of HTLV-I-induced myeloneuropathy in rats.


Assuntos
Oligodendroglia/metabolismo , Paraparesia Espástica Tropical/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/fisiologia , Animais , Morte Celular , Células Cultivadas , Regulação para Baixo , Produtos do Gene tax/metabolismo , Imuno-Histoquímica , Microglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Receptores do Fator de Necrose Tumoral/metabolismo , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
10.
Acta Neuropathol ; 97(2): 107-12, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9928820

RESUMO

To investigate the pathogenetic role of human T lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, has been established. Wistar-King-Aptekman-Hokudai strain rats with induced HTLV-I infection develop a chronic progressive myeloneuropathy with paraparesis of hind limbs after an incubation period of 15 months. In the affected spinal cord in these rats, white matter degeneration, demyelination and vacuolar change with microglia/macrophage infiltration are present as are the provirus DNA and the virus mRNA. To identify infected cells in the affected lesions, we carried out in situ hybridization of amplified fragments of the provirus DNA by polymerase chain reaction on thin sections, plus immunohistochemistry on the same sections. The provirus DNA was localized in some microglia/macrophages in the spinal cord lesion. In addition, the HTLV-I provirus was clearly evident not only in ED-1-negative lymphoid cells but also in ED-1-positive macrophages from lymph nodes. These observations suggest that cells of microglia/macrophage lineage may be one of dominant viral reservoirs in the spinal cords and lymph nodes in HAM rat disease. These infected microglia/macrophages may relate to cause the myeloneuropathy through neurotoxic cytokine synthesis.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Macrófagos/virologia , Microglia/virologia , Paraparesia Espástica Tropical/virologia , Medula Espinal/virologia , Animais , Núcleo Celular/virologia , DNA Viral/isolamento & purificação , Modelos Animais de Doenças , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfonodos/virologia , Reação em Cadeia da Polimerase , Provírus/isolamento & purificação , Ratos , Ratos Endogâmicos
12.
Leukemia ; 11 Suppl 3: 245-6, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9209354

RESUMO

To examine the pathogenic roles of HTLV-I in HTLV-I-induced diseases, we developed two models; namely HTLV-I carrier rats and HTLV-I env-pX transgenic rats. Among life long HTLV-I carriers in seven rat strains, only WKAH rats with the RT1k haplotype developed chronic progressive myeloneuropathy, resembling HAM/TSP clinically and histologically in humans, designated as HAM rat disease and after long incubation periods. Apoptosis of myelin forming cells, oligodendrocytes and Schwann cells associated with HTLV-I infection appears to be the primary cause of HAM rat disease. Local activation of the pX gene and TNF alpha gene was evident in these rats. WKAH rats transgenic for HTLV-I env-pX gene were established and at age 5 weeks, swelling of the bilateral ankle joints began to develop and histological features of the affected joints resembled findings in cases of rheumatoid arthritis (RA): high-titers of rheumatoid factors were present in these rats. A series of vascular collagen diseases such as polyarteritis nodosa-like angiitis, polymyositis, myocarditis, and Sjögren's syndrome-like sialodenitis together with RA were present, even in one individual animal. These transgenic rats as well as HAM rats appear to be suitable animal models for elucidating pathogenic mechanisms implicated in HTLV-I-induced diseases and also various demyelinating vascular collagen diseases of unknown etiology.


Assuntos
Genes env , Infecções por HTLV-I/transmissão , Vírus Linfotrópico T Tipo 1 Humano/genética , Paraparesia Espástica Tropical/transmissão , Proteínas Oncogênicas de Retroviridae/genética , Fatores de Transcrição , Animais , Animais Geneticamente Modificados , Artrite Reumatoide/fisiopatologia , Portador Sadio , Modelos Animais de Doenças , Regulação da Expressão Gênica , Produtos do Gene env/biossíntese , Produtos do Gene env/genética , Infecções por HTLV-I/fisiopatologia , Paraparesia Espástica Tropical/fisiopatologia , Ratos , Ratos Endogâmicos , Proteínas Oncogênicas de Retroviridae/biossíntese , Fator Reumatoide/análise , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Virais Reguladoras e Acessórias
13.
Leukemia ; 11 Suppl 3: 255-7, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9209357

RESUMO

To investigate the pathogenesis of HTLV-I associated diseases, we established a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in WKAH rats. In the spinal cords of WKAH rats carrying HTLV-I, chronological histopathology revealed the occurrence of apoptotic cell death starting at 9 months after the infection, followed by demyelination, macrophage infiltration, and the activation of astrocytes starting at 12, 15 and 20 months, respectively. Apoptosis of the Schwann cells was also observed in the peripheral nerves of these rats. By RT-PCR, pX mRNA of HTLV-I was selectively expressed in the diseased spinal cords and peripheral nerves, but not in the unaffected cerebra, cerebella, even though provirus DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of TNF-alpha were frequently detected in the spinal cord and the cerebrospinal fluid. The collective evidence suggests that the selective activation of HTLV-I, in particular Tax expression, and/or the production of TNF-alpha in target spinal cord and peripheral nerves are causally related to apoptotic death of the oligodendrocytes and Schwann cells, a major pathogenetic pathway of HTLV-I induced myeloneuropathy in the WKAH rat.


Assuntos
Encéfalo/patologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Paraparesia Espástica Tropical/fisiopatologia , Nervos Periféricos/patologia , Proteínas Oncogênicas de Retroviridae/biossíntese , Medula Espinal/patologia , Fatores de Transcrição , Fator de Necrose Tumoral alfa/biossíntese , Animais , Apoptose , Astrócitos/patologia , Encéfalo/metabolismo , DNA Viral/biossíntese , Regulação da Expressão Gênica , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Bainha de Mielina/patologia , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/patologia , Nervos Periféricos/metabolismo , Reação em Cadeia da Polimerase , Provírus/isolamento & purificação , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos , Proteínas Oncogênicas de Retroviridae/genética , Células de Schwann/patologia , Medula Espinal/metabolismo , Fatores de Tempo , Transcrição Gênica , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/genética , Proteínas Virais Reguladoras e Acessórias , Replicação Viral
14.
J Infect Dis ; 174(2): 318-23, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8699061

RESUMO

The pathogenetic roles of human T lymphocyte virus type I (HTLV-I) and cytokines were investigated in HTLV-I-induced myeloneuropathy in Wistar-King-Aptekman-Hokudai rats. In the nervous system, pX messenger RNAs of HTLV-I were selectively expressed in the diseased spinal cord and peripheral nerves but not in the unaffected cerebrum and cerebellum, even though proviral DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of tumor necrosis factor (TNF)-alpha in the spinal cord and cerebrospinal fluid correlated positively with the development of spinal cord lesions. The collective evidence strongly suggests that selective activation of HTLV-I, in particular Tax expression and production of TNF-alpha induced by HTLV-I infection in target spinal cord and peripheral nerves, is causally related to apoptotic death of oligodendrocytes and Schwann cells, a major pathogenetic pathway of the HTLV-I-induced myeloneuropathy.


Assuntos
Apoptose , Genes pX , Neuroglia , Paraparesia Espástica Tropical/etiologia , Fator de Necrose Tumoral alfa/genética , Animais , Sequência de Bases , Portador Sadio , Modelos Animais de Doenças , Dados de Sequência Molecular , Oligodendroglia , Nervos Periféricos/virologia , Ratos , Ratos Endogâmicos Lew , Células de Schwann , Nervo Isquiático/virologia , Medula Espinal/virologia , Distribuição Tecidual , Ativação Transcricional , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Integração Viral
15.
Nihon Rinsho ; 52(11): 2926-31, 1994 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-7996691

RESUMO

We have established a model of HTLV-I infection in the WKAH rat strain. By inoculating MT-2, an HTLV-I producing human T cell line, HAM rat disease, a demyelinating disease resembling human HAM/TSP, developed in the WKAH rat strain. The affected lesion in the HAM rat disease is distributed symmetrically in the lateral and anterior funiculi of the thoratic spinal cord similar to that of HAM/TSP, and the histological features are also mimicked except for infiltration of lymphocytes. Using this model, it is suggested that the apoptosis of oligodendrocyte appears to be the most important process implicated in the demyelinating process of the spinal cord. The pathogenesis of HAM/TSP is also discussed herein.


Assuntos
Paraparesia Espástica Tropical , Animais , Modelos Animais de Doenças , Ratos , Ratos Endogâmicos
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