Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Transpl Int ; 19(12): 1014-21, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17081232

RESUMO

Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common gamma chain. The rationally designed inhibitor of JAK3, CP-690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP-690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1(a)) or Lewis (RT1(l)) rats were heterotopically transplanted into the infra-renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP-690,550 by osmotic pumps (mean drug exposure of 110 +/- 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 +/- 0.85% vs. 0.43 +/- 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 +/- 2.4% vs. 0.38 +/- 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP-690,550-treated animals also had a significant reduction of donor-specific IgG production and of the gene expression for suppressor of cytokine signaling-3 and with unchanged levels of expression of RANTES, IP-10 and transforming growth factor-beta1. These results are the first to show that JAK3 blockade by CP-690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.


Assuntos
Aorta/transplante , Arteriosclerose/prevenção & controle , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Quimiocina CCL5/genética , Hiperplasia , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Masculino , Piperidinas , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Transplante Homólogo , Túnica Íntima/patologia
2.
Transplantation ; 80(12): 1756-64, 2005 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-16378072

RESUMO

BACKGROUND: Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). METHODS: Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. RESULTS: Mean survival time (+/-SEM) in animals treated with MMF alone (23+/-1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5+/-9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2+/-8.7 days) than animals that received less CP-690,550 (33.3+/-12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. CONCLUSIONS: Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim/imunologia , Ácido Micofenólico/análogos & derivados , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Janus Quinase 3 , Macaca fascicularis , Modelos Animais , Ácido Micofenólico/uso terapêutico , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo
3.
Transplantation ; 80(9): 1283-92, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16314797

RESUMO

BACKGROUND: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates. METHODS: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry. RESULTS: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected. CONCLUSIONS: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.


Assuntos
Sistema Imunitário/patologia , Sistema Imunitário/fisiologia , Transplante de Rim/imunologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Interferon gama/biossíntese , Interleucina-2/metabolismo , Janus Quinase 3 , Células Matadoras Naturais/patologia , Contagem de Leucócitos , Ativação Linfocitária/efeitos dos fármacos , Macaca fascicularis , Masculino , Piperidinas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
4.
Atherosclerosis ; 181(2): 407-9, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15998518

RESUMO

Arterial obstruction due to intimal myproliferation is an outcome used for investigating chronic allograft vasculopathy in animal models. Since harvested tissue may be distorted while processing, discrepancy may happen in the measure of the obstruction. We propose a standardized micromorphometric method for calculating the percentage of obstruction with eliminating the variability in the shape of the vessel cross-section. The mathematical adjustment avoids the overestimation of the percentage of obstruction and improves accuracy.


Assuntos
Oclusão de Enxerto Vascular/patologia , Rejeição de Enxerto/patologia , Microscopia/métodos , Microscopia/normas , Animais , Aorta/patologia , Aorta/transplante , Doença Crônica , Modelos Animais de Doenças , Modelos Biológicos , Ratos , Transplante Homólogo
5.
J Surg Res ; 124(2): 280-8, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15820259

RESUMO

BACKGROUND: Strategies to induce donor-specific allograft tolerance are best tested in preclinical models developed in nonhuman primates (NHPs). Most protocols prepare the recipient by infusing hematopoietic cells from the donor. We report here a procedure to isolate and characterize large numbers of bone marrow cells (BMCs) from cynomolgus monkeys (cynos) that can then successfully be transplanted into conditioned recipients. MATERIALS AND METHODS: Vertebral columns of five cynos were excised en bloc and separated into individual vertebrae. The cancelous bone was extracted with a core puncher, fractionated, filtered, centrifuged, and resuspended in transplantation media before being analyzed by flow cytometry. In two instances, the collected BMCs were reinfused into allogeneic recipients preconditioned with a nonmyeloablative regimen. Chimerism was monitored using short-tandem repeat analysis. RESULTS: The mean total BMCs yield was 25.5 x 10(9) (range of 4.00 x 10(9) to 59 x 10(9)) with mean cell viability of 93.4% (range: 90-96%). CD34+ cells and CD3+ cells averaged 0.34 and 3.91% of total BMCs, respectively. This resulted in absolute cell number yields of 1.02 x 10(8) and 1.15 x 10(9) for CD34+ and CD3+ cells, respectively. Graft-versus-host disease was absent in both bone marrow infused animals, and a maximum level of chimerism of 18% was detected at 3 weeks after BMCs infusion. CONCLUSION: We present here the first detailed report of a procedure to retrieve and characterize large numbers of BMCs from vertebral bodies of cynos and demonstrate that cells collected with this technique have the capability of engrafting in allogenic recipients.


Assuntos
Células da Medula Óssea/citologia , Separação Celular/métodos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Coluna Vertebral/citologia , Animais , Células da Medula Óssea/imunologia , Rejeição de Enxerto/tratamento farmacológico , Células-Tronco Hematopoéticas/imunologia , Tolerância Imunológica , Imunossupressores/farmacologia , Macaca fascicularis , Masculino , Quimeras de Transplante , Transplante Homólogo
6.
Transplantation ; 79(7): 791-801, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15818321

RESUMO

BACKGROUND: Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. METHODS: Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection. RESULTS: Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. CONCLUSIONS: CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Transplante de Rim/imunologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Citometria de Fluxo , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Janus Quinase 3 , Rim/efeitos dos fármacos , Rim/fisiopatologia , Contagem de Leucócitos , Linfócitos/imunologia , Macaca fascicularis , Piperidinas , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/farmacocinética , Pirróis/uso terapêutico , Fatores de Tempo , Transplante Homólogo
7.
Arch Pathol Lab Med ; 126(3): 369-71, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11860318

RESUMO

Biliary papillomatosis is a rare entity characterized by multiple papillary adenomas involving extensive areas of the biliary tract with a great potential for recurrence and malignant transformation. It has been reported in association with Caroli disease and a choledochal cyst. We report herein a case of malignant intrahepatic biliary papillomatosis associated with cirrhosis secondary to hepatitis C. To the best of our knowledge, this is the first report of this association.


Assuntos
Ductos Biliares Intra-Hepáticos/patologia , Neoplasias do Sistema Biliar/patologia , Hepatite C/patologia , Cirrose Hepática/patologia , Papiloma/patologia , Adenocarcinoma/complicações , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adenoma de Ducto Biliar/complicações , Adenoma de Ducto Biliar/patologia , Adenoma de Ducto Biliar/cirurgia , Idoso , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/cirurgia , Evolução Fatal , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Neoplasias Pulmonares/secundário , Masculino , Papiloma/complicações , Papiloma/cirurgia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...