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1.
Viruses ; 12(5)2020 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-32456286

RESUMO

Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and mortality by the FIP virus (FIPV, virulent feline coronavirus). Several antiviral drugs for FIP have been identified, but many of these are expensive and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. We investigated whether HCQ in association with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 µM of HCQ significantly inhibited the replication of types I and II FIPV. Interestingly, the combination of 100 µM of HCQ and 104 U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω are applicable for treatment of FIP. Further clinical studies are needed to verify the combination of HCQ and rIFN-ω will be effective and safe treatment for cats with FIP.


Assuntos
Antivirais/farmacologia , Coronavirus Felino/efeitos dos fármacos , Hidroxicloroquina/farmacologia , Interferon Tipo I/farmacologia , Análise de Variância , Animais , Antivirais/uso terapêutico , Antivirais/toxicidade , Gatos , Linhagem Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavirus Felino/patogenicidade , Combinação de Medicamentos , Peritonite Infecciosa Felina/tratamento farmacológico , Peritonite Infecciosa Felina/virologia , Imunofluorescência/veterinária , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/toxicidade , Interferon Tipo I/uso terapêutico , Interferon Tipo I/toxicidade , Virulência
2.
J Neurosci ; 40(18): 3517-3532, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245829

RESUMO

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.


Assuntos
Viroses do Sistema Nervoso Central/metabolismo , Interferon Tipo I/toxicidade , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Células Cultivadas , Viroses do Sistema Nervoso Central/induzido quimicamente , Viroses do Sistema Nervoso Central/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
3.
Brain ; 141(6): 1609-1621, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29741608

RESUMO

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.


Assuntos
Dermatomiosite , Interferon Tipo I/toxicidade , Inibidores de Janus Quinases/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Pirazóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Transformada , Dermatomiosite/induzido quimicamente , Dermatomiosite/tratamento farmacológico , Dermatomiosite/patologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Neovascularização Patológica/induzido quimicamente , Nitrilas , Pirimidinas , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 107(7): 3012-7, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20133703

RESUMO

Glomerulonephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Although substantial progress has been made in the identification of pathogenic triggers that result in autoantibody production, little is known about the pathogenesis of aggressive proliferative processes that lead directly to irreversible glomerular damage and compromise of renal function. In this study, we describe a model of polyinosinic: polycytidylic acid-accelerated lupus nephritis in NZB/W mice that is characterized by severe glomerular proliferative lesions with de novo crescent formation, findings that are linked with decreased survival and adverse outcomes in lupus. Proliferative glomerulonephritis was associated with infiltrating kidney macrophages and renal expression of IFN-inducible genes, matrix metalloproteinases (MMPs), and growth factors. Crescent formation and renal MMP and growth factor expression were dependent on renal macrophages that expressed Il10, MMPs, osteopontin, and growth factors, including Pdgfc and Hbegf. Infiltrating macrophages and renal MMP expression were induced by type I IFN. These findings reveal a role for type I IFNs and alternatively activated macrophages in aggressive proliferative lesions of lupus nephritis.


Assuntos
Regulação da Expressão Gênica/imunologia , Interferon Tipo I/metabolismo , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/fisiopatologia , Macrófagos/metabolismo , Metaloproteases/metabolismo , Poli I-C/metabolismo , Proteinúria/induzido quimicamente , Animais , Eletroforese em Gel de Poliacrilamida , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Immunoblotting , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon Tipo I/toxicidade , Interleucina-10/metabolismo , Nefrite Lúpica/enzimologia , Nefrite Lúpica/imunologia , Linfocinas/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Osteopontina/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Poli I-C/toxicidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas
5.
Drug Chem Toxicol ; 30(1): 83-95, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17364866

RESUMO

HM10620 is a recombinant human interferon-alpha (rhIFN-alpha) linked to immunoglobulin via N-terminal-specific non-peptidyl polyethylene glycol linker to improve the in vivo stability of interferon. Potential genotoxic effects of HM10620 in three short-term mutagenicity assays were investigated, which included the Ames assay, in vitro chromosomal aberration assay, and the in vivo micronucleus assay. HM10620 did not cause any mutation in the Ames assay tested using five tester strains at six concentrations of 6.25, 12.5, 25, 50, 100, and 200 microg/plate. To assess clastogenic effect, the in vitro chromosomal aberration assay and the in vivo micronucleus assay were performed using Chinese hamster lung cells and male ICR mice, respectively. Chromosomal aberration was not induced at the concentrations of 10, 20, and 40 microg/mL. Also, there was no difference in the incidence of micronucleated polychromatic erythrocytes at doses of 10, 20, and 40 mg/kg in male mice compared with the vehicle control group. Therefore, based on the results obtained from the three studies, it is concluded that HM10620 is not a mutagenic agent in bacterial cells and causes no chromosomal damage in mammalian cells both in vitro and in vivo.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Eritrócitos/efeitos dos fármacos , Interferon Tipo I/toxicidade , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Imunoglobulinas/química , Interferon Tipo I/química , Interferon-alfa , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Mutagenicidade , Proteínas Recombinantes de Fusão , Proteínas Recombinantes , Organismos Livres de Patógenos Específicos
6.
Basic Clin Pharmacol Toxicol ; 99(1): 62-70, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16867173

RESUMO

Human omega-interferon (IFN-omega) has been shown to be well-tolerated in man and to induce reductions of hepatitis C virus RNA levels in a series of human clinical trials. Here we provide an overview of our preclinical safety evaluation of the fully-glycosylated human IFN-omega produced from CHO-SS cells that is currently being evaluated clinically. IFN-omega was not associated with any biologically-relevant adverse effects in a series of 10 safety pharmacology experiments, in the Ames mutagenicity test, in the micronucleus test, or in intraarterial, intravenous, paravenous or subcutaneous local tolerance studies. Acute, subacute, subchronic and reproductive toxicity studies performed in cynomolgus monkeys and rats showed a toxicity profile similar to that of human alpha interferon (IFN-alpha). Except for the acute (single-dose) toxicology study, all of the other toxicity studies showed evidence for the formation of anti-IFN-omega antibodies over time in the animals. These antibodies were found to neutralize IFN-omega antiviral activity in vitro in a dose-dependent manner. The average pharmacokinetic parameters following a single subcutaneous dose of IFN-omega in rabbits, rats and monkeys were determined and found to be similar to that of human IFN-alpha. These findings demonstrate that IFN-omega has a safety profile consistent with that required for its use in man. IFN-omega might be beneficial for the treatment of patients infected with hepatitis C virus who fail to respond to IFN-alpha or as a first-line treatment option.


Assuntos
Antivirais/farmacologia , Interferon Tipo I/farmacologia , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Células CHO , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Cricetinae , Ensaio de Imunoadsorção Enzimática , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Injeções Subcutâneas , Interferon Tipo I/farmacocinética , Interferon Tipo I/toxicidade , Testes de Função Renal , Testes de Função Hepática , Macaca fascicularis , Camundongos , Atividade Motora/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/toxicidade , Testes de Neutralização , Gravidez , Coelhos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/toxicidade , Reprodução , Testes de Função Respiratória
8.
J Interferon Cytokine Res ; 24(4): 231-43, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15144569

RESUMO

Various human colon cancer cell lines tested in vitro differed significantly in susceptibility to growth inhibition of recombinant human interferon-beta (rHuIFN-beta). Two p53-mutant lines, COH and CC-M2, derived from high-grade colon adenocarcinoma, showed signs of apoptosis after treatment with 250 IU/ml of HuIFN- beta in the culture medium. The similarly p53-mutated HT-29 line from a grade I adenocarcinoma showed no apoptosis, however, and only cell cycle G1/G0 or S phase retardation with 1000 IU/ml HuIFN-beta. After HuIFN-beta exposure, COH and CC-M2 cells showed increased levels of Fas and FasL proteins, alteration of mitochondrial membrane potential, and activation of caspase-9, caspase-8, and caspase-3 in a time-dependent manner. Treatment of COH and CC-M2 cells with anti-FasL antibodies or rFas/Fc fusion protein, however, could not prevent the apoptosis induced by HuIFN-beta. In contrast, cell-permeable specific inhibitors of the three caspases could inhibit the DNA fragmentation and cell death but not the mitochondrial membrane potential changes. Treatment with mitochondria-stabilizing reagents could significantly abrogate the apoptosis and caspase activation induced by HuIFN-beta. These results suggest that in COH and CC-M2 colon cancer cell lines, HuIFN-beta induces apoptosis mainly through mitochondrial membrane alteration and subsequent activation of the caspase cascade pathway, but not by the Fas/FasL interaction or the p53-dependent apoptotic mechanism.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Interferon Tipo I/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2 , Receptores do Fator de Necrose Tumoral , Adenocarcinoma/enzimologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/toxicidade , Inibidores de Caspase , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Citocromos c/metabolismo , Ativação Enzimática/efeitos dos fármacos , Proteína Ligante Fas , Genes p53/genética , Humanos , Interferon Tipo I/toxicidade , Glicoproteínas de Membrana/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mutação/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Recombinantes , Proteína X Associada a bcl-2 , Receptor fas
9.
Clin Cancer Res ; 9(4): 1354-60, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12684404

RESUMO

PURPOSE: The purpose of our study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs) of consensus IFN (CIFN). EXPERIMENTAL DESIGN: Cohorts of three to six patients with metastatic renal cell carcinoma (RCC) were treated with escalating doses of CIFN (dose level I, 9.0 microg/m(2); dose level II, 15.0 microg/m(2); dose level III, 21.0 microg/m(2)) given s.c. three times weekly in 4-week cycles until progression. The cohort treated at the maximum tolerated dose was expanded to further define toxicity. An additional three patients were treated with i.v. CIFN (15.0 microg/m(2)) to evaluate route-related differences in gene expression. Cytokine and chemokine gene expression in PBMCs was assessed by reverse transcription-PCR. RESULTS: A total of 25 patients (18 men and 7 women) were enrolled between January 28, 1999, and November 1, 2000, at dose levels I (n = 4), II (n = 14), and III (n = 7). Dose-limiting toxicity occurred at dose level III (21 microg/m(2)) and included grade-3 or -4 respiratory distress/failure (n = 3) and hypocalcemia (n = 1) occurring within the first cycle of treatment. Other severe toxicities included grade-3 neutropenia, thrombocytopenia, fatigue, and nausea/vomiting. Studies of cytokine and chemokine gene expression in PBMCs from eight patients revealed induction of IFN-gamma, IP-10, and Mig. I.V. administration was associated with a faster induction, but of shorter duration. There were no responses; however, 24 patients had stable disease of variable duration (4-32 weeks) and received a median of three cycles of treatment (range, 1-8 cycles). Overall median survival was 13.5 months, and was 12.7 months in the previously treated patients. CONCLUSION: CIFN was safely administered s.c. three times weekly at doses up to 15.0 microg/m(2). Although there were no responses, the median survival was longer than expected in a previously treated patient population with metastatic RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interferon Tipo I/toxicidade , Interferon Tipo I/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Southern Blotting , Carcinoma de Células Renais/patologia , Feminino , Humanos , Interferon-alfa , Interferon gama/metabolismo , Neoplasias Renais/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
J Interferon Cytokine Res ; 18(9): 731-7, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9781812

RESUMO

Type I interferons (IFN), including IFN-alpha and IFN-beta, cause severe lymphopenia, resulting from altered lymphocyte recirculation and redistribution. IFN-tau, a product of trophectoderm of ruminant conceptuses and new member of the type I IFN family has not been examined for its effect on leukocyte recirculation. Additionally, differential effects of type I IFNs on the redistribution and recirculation of subsets of T cells have not been reported. The present study determined the effects of IFN-tau on the redistribution and recirculation of ovine leukocytes and T cell subsets. Total peripheral blood leukocytes, lymphocytes, and segmented neutrophils were reduced (p < 0.05) following treatment of lambs with IFN-tau. Furthermore, administration of IFN-tau caused an acute, differential reduction in peripheral blood CD4+ T cells (p < 0.05), CD5+ cells (p < 0.05), and gammadelta TCR+ (p < 0.01) T cells but had no effect on CD8+ T cells (p > 0.05). IFN-tau reduced the percentage of gammadelta T cells by 8-fold and that of CD4+ T cells and CD5+ cells by <2-fold in peripheral blood when compared with control lambs. The reduction in leukocytes, lymphocytes, and neutrophils was observed as early as 6-12 h after administration of IFN-tau, but levels returned to control values within 48 h. These results indicate that IFN-tau, like other members of the type I IFN family, can have immediate effects on leukocyte recirculation and redistribution. The present study is the first to demonstrate that IFN-tau differentially regulates T cell recirculation with the greatest effect on gammadelta TcR+ T cells.


Assuntos
Interferon Tipo I/toxicidade , Linfopenia/induzido quimicamente , Neutropenia/induzido quimicamente , Proteínas da Gravidez/toxicidade , Trofoblastos/metabolismo , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Citometria de Fluxo , Contagem de Leucócitos/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Proteínas Recombinantes/toxicidade , Ovinos
12.
Res Virol ; 148(5): 353-65, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9403935

RESUMO

Sandfly fever Sicilian virus (SFSV) was used in our laboratory to screen antiviral substances active toward viruses of the Bunyaviridae family. Antiviral activity was estimated by the reduction of the cytopathic effect of SFSV on infected Vero cells. Cytotoxicity was evaluated by determining the inhibition of Trypan blue exclusion. The specificity of action of each tested compound was estimated by the selectivity index (CD50/ED50). Selectivity indices of human recombinant interferon-alpha (IFN alpha) (Roferon and Introna), iota-, kappa- and lambda- carrageenans, fucoidan and 6-azauridine were much higher than that of ribavirin, the only antiviral substance which has been previously investigated for its inhibitory effects on Phlebovirus infections. Other compounds showed significant antiviral activity: glycyrrhizin, suramin sodium, dextran sulphate and pentosan polysulphate. All these compounds caused a concentration-dependent reduction in the virus yield. Ribavirin, 6-azauridine and IFN alpha have been shown to inhibit a late step of the virus replicative cycle, whereas glycyrrhizin and suramin sodium were active at an early step and the sulphated polysaccharides inhibited adsorption of SFSV on the cells. The antiviral compounds selected in this study as specific inhibitors of in vitro replication of SFSV are promising candidates for the chemotherapy of haemorrhagic fevers caused by viruses of the Bunyaviridae family. The combination of IFN alpha and ribavirin, which showed a synergistic antiviral effect, should be evaluated for the treatment of these infections.


Assuntos
Antivirais/farmacologia , Phlebovirus/efeitos dos fármacos , Animais , Antivirais/toxicidade , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interferon Tipo I/farmacologia , Interferon Tipo I/toxicidade , Phlebovirus/crescimento & desenvolvimento , Phlebovirus/fisiologia , Psychodidae/virologia , Proteínas Recombinantes , Ribavirina/farmacologia , Ribavirina/toxicidade , Fatores de Tempo , Células Vero , Replicação Viral/efeitos dos fármacos
13.
Biol Reprod ; 57(3): 621-9, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9283000

RESUMO

Interferon tau (IFN tau) is the conceptus-produced antiluteolytic signal in ruminants. Three experiments examined the effects of s.c. administration of recombinant ovine (ro)IFN tau on interestrous interval (IEI), oxytocin (OT)-induced uterine prostaglandin F2alpha metabolite (PGFM) production, rectal temperature (RT), respiration rate (RR), and plasma concentrations of progesterone, cortisol, LH, and antiviral activity (AVA) in plasma and uterine flushings. In experiment I, 20 ewes were treated s.c. with either 0, 1, 2, or 4 mg/day roIFN tau (0.7 x 10(8) U/mg; 5 ewes/dosage) from Days 11 to 15 of the estrous cycle (estrus = Day 0) and were challenged with OT (30 IU) on Day 15. Jugular blood samples were collected at -10, 0, 10, 20, 30, 40, 50, and 60 min relative to the OT challenge and assayed for PGFM. Recombinant oIFN tau increased IEI (16.7, 18.7, and 22.6 +/- 0.6 days for 0, 2, and 4 mg roIFN tau, respectively, p < 0.01). Recombinant oIFN tau did not affect peak PGFM response to OT (2309 +/- 172 pg/ml; p > 0.1). However, the 4 mg/day dosage delayed the time to peak PGFM (32.4 vs. 47.5 +/- 3.4 min; p < 0.01, 0 vs. 4 mg) and resulted in approximately 200% higher concentrations of PGFM at 60 min post-OT (0 vs. 4 mg/day, p < 0.07). Experiment II was similar to experiment I, except that only the 0- and 4-mg/day dosages of roIFN tau were administered. Ewes were hysterectomized on Day 16, and assay of uterine flushes detected no AVA from ewes treated with either 0 or 4 mg/day roIFN tau. In experiment III, 20 ewes were treated s.c. with either 0, 2, 4, or 6 mg roIFN tau on Day 12. Blood samples, RT, and RR were obtained at frequent intervals for 24 h, and plasma was assayed for progesterone, cortisol, LH, and AVA. Plasma AVA, which increased in a dose-dependent manner, was detectable within 60 min and remained elevated at 24 h compared to control values. RT (elevated 0.5-1.0 degrees C), RR, and cortisol increased in response to all dosages of roIFN tau, with peak values occurring 150-180 min postinjection. For all dosages of roIFN tau, plasma progesterone declined from 120 to 360 min posttreatment and then returned to pretreatment values by 24 h (p < 0.01) as compared to controls. Overall, exogenous roIFN tau altered uterine PGFM response to OT from a pulse to a gradual and sustained elevation and extended IEI with only a transient decline in progesterone and mild hyperthermia, effects that are not expected to compromise pregnancy.


Assuntos
Estro/efeitos dos fármacos , Hormônios/sangue , Interferon Tipo I/farmacologia , Proteínas da Gravidez/farmacologia , Útero/efeitos dos fármacos , Animais , Antivirais/sangue , Temperatura Corporal/efeitos dos fármacos , Dinoprosta/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Fertilidade/efeitos dos fármacos , Hidrocortisona/sangue , Interferon Tipo I/administração & dosagem , Interferon Tipo I/toxicidade , Hormônio Luteinizante/sangue , Ocitocina/farmacologia , Gravidez , Proteínas da Gravidez/administração & dosagem , Proteínas da Gravidez/toxicidade , Progesterona/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/toxicidade , Ovinos , Útero/metabolismo
14.
Proc Natl Acad Sci U S A ; 92(26): 12270-4, 1995 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-8618883

RESUMO

Interferon tau (IFN tau), originally identified as a pregnancy recognition hormone, is a type I interferon that is related to the various IFN alpha species (IFN alpha s). Ovine IFN tau has antiviral activity similar to that of human IFN alpha A on the Madin-Darby bovine kidney (MDBK) cell line and is equally effective in inhibiting cell proliferation. In this study, IFN tau was found to differ from IFN alpha A in that is was > 30-fold less toxic to MDBK cells at high concentrations. Excess IFN tau did not block the cytotoxicity of IFN alpha A on MDBK cells, suggesting that these two type I IFNs recognize the type I IFN receptor differently on these cells. In direct binding studies, 125I-IFN tau had a Kd of 3.90 x 10(-10) M for receptor on MDBK cells, whereas that of 125I-IFN alpha A was 4.45 x 10(-11) M. Consistent with the higher binding affinity, IFN alpha A was severalfold more effective than IFN tau in competitive binding against 125I-IFN tau to receptor on MDBK cells. Paradoxically, the two IFNs had similar specific antiviral activities on MDBK cells. However, maximal IFN antiviral activity required only fractional occupancy of receptors, whereas toxicity was associated with maximal receptor occupancy. Hence, IFN alpha A, with the higher binding affinity, was more toxic than IFN tau. The IFNs were similar in inducing the specific phosphorylation of the type I receptor-associated tyrosine kinase Tyk2, and the transcription factors Stat1 alpha and Stat2, suggesting that phosphorylation of these signal transduction proteins is not involved in the cellular toxicity associated with type I IFNs. Experiments using synthetic peptides suggest that differences in the interaction at the N terminal of IFN tau and IFN alpha with the type I receptor complex contribute significantly to differences in high-affinity equilibrium binding of these molecules. It is postulated that such a differential recognition of the receptor is responsible for the similar antiviral but different cytotoxic effects of these IFNs. Moreover, these data imply that receptors are "spare'' with respect to certain biological properties, and we speculate that IFNs may induce a concentration-dependent selective association of receptor subunits.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Interferon Tipo I/metabolismo , Interferon Tipo I/toxicidade , Proteínas da Gravidez/metabolismo , Proteínas da Gravidez/toxicidade , Proteínas Tirosina Quinases , Receptores de Interferon/metabolismo , Animais , Ligação Competitiva , Linfoma de Burkitt , Bovinos , Linhagem Celular , Proteínas de Ligação a DNA/isolamento & purificação , Proteínas de Ligação a DNA/metabolismo , Humanos , Rim , Cinética , Proteínas de Membrana , Fosforilação , Proteínas/metabolismo , Receptor de Interferon alfa e beta , Proteínas Recombinantes , Fator de Transcrição STAT1 , Fator de Transcrição STAT2 , TYK2 Quinase , Transativadores/isolamento & purificação , Transativadores/metabolismo , Células Tumorais Cultivadas
15.
J Immunol ; 155(5): 2747-53, 1995 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-7544384

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease if the central nervous system (CNS). Recently, the type I IFN, IFN-beta-1b was demonstrated to be a useful immunotherapy for MS. During treatment with IFN-beta-1b, toxicity at higher doses has been observed. IFN-tau, discovered for its role in the reproductive cycle, possesses all of the functions normally ascribed to the type I IFNs but lacks the toxicity normally associate with IFN treatment in vitro. We have examined the effects of IFN-tau treatment on experimental allergic encephalomyelitis (EAE), an animal model useful for the study of MS. EAE is a model of Ag-induced autoimmunity that can be modulated by bacterial superantigen to resemble the relapsing-remitting pattern of autoimmune disease observed in MS. IFN-tau was able to prevent development of EAE as effectively as IFN-beta but without associated toxicity such as lymphocyte suppression and weight loss. In addition, IFN-tau was able to prevent superantigen reactivation of EAE akin to the reduction in disease exacerbations observed in IFN-beta-1b treated MS patients. Mechanisms by which IFN-tau may prevent EAE include reduced proliferation in response to the autoantigen myelin basic protein and reduced TNF-alpha production. Thus, IFN-tau may prove to be a promising new IFN therapy for MS in light of its ability to prevent EAE and the lack of toxicity exhibited by this novel IFN.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Interferon Tipo I/farmacologia , Interferon Tipo I/toxicidade , Proteínas da Gravidez/farmacologia , Proteínas da Gravidez/toxicidade , Superantígenos/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos , Proteína Básica da Mielina/efeitos dos fármacos , Proteína Básica da Mielina/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Ovinos , Superantígenos/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
16.
J Clin Oncol ; 13(2): 497-501, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7844611

RESUMO

PURPOSE: In a phase II multiinstitutional outpatient trial, patients with progressive metastatic renal cell carcinoma were treated with a combination of subcutaneous (SC) recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2 (rIFN alpha 2). PATIENTS AND METHODS: One hundred fifty-two patients with metastatic renal cell carcinoma were treated. Treatment courses consisted of SC rIL-2 at 20 x 10(6) IU/m2 three times per week in weeks 1 and 4, and at 5 x 10(6) IU/m2 three times per week in weeks 2, 3, 5, and 6. Additionally, patients received SC rIFN alpha 2 6 x 10(6) U/m2 once per week in weeks 1 and 4, and three times per week in weeks 2, 3, 5, and 6. RESULTS: There were nine (6%) complete responses (CRs) and 29 (19%) partial responses (PRs), for an overall response rate of 25% (95% confidence interval, 19% to 32%). The median duration of responses for CRs and PRs was 16+ and 9 months, respectively. Additionally, 55 patients (36%) had stable disease (SD). Fifty-nine patients (39%) had continued disease progression (PD) despite treatment, or went off study after less than 4 weeks of therapy. The majority of patients treated experienced fever, chills, malaise, nausea, vomiting, and anorexia, side effects that were mostly limited to World Health Organization (WHO) grade 1 and 2. However, one patient developed grade 4 CNS toxicity with extended somnolence. On cessation of therapy, the neurologic symptoms in this patient were fully reversible, with no neurologic deficiency. CONCLUSION: In summary, this multiinstitutional home-therapy setting of SC rIL-2 and SC rIFN alpha 2 in patients with progressive metastatic renal cell carcinoma demonstrated drastically reduced systemic toxicity, while it confirmed the therapeutic efficacy of the low-dose SC immunotherapy combination schedule.


Assuntos
Carcinoma de Células Renais/terapia , Interferon Tipo I/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Adulto , Idoso , Esquema de Medicação , Quimioterapia Combinada , Tolerância a Medicamentos , Feminino , Humanos , Injeções Subcutâneas , Interferon Tipo I/administração & dosagem , Interferon Tipo I/toxicidade , Interleucina-2/administração & dosagem , Interleucina-2/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pacientes Ambulatoriais , Proteínas Recombinantes , Segurança , Fatores de Tempo , Resultado do Tratamento
17.
Br J Cancer ; 69(6): 1111-4, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8198979

RESUMO

A double-institution phase II study was performed in patients with metastatic renal cell carcinoma treated subcutaneously (s.c.) with interleukin 2 (IL-2) and alpha-interferon (INF-alpha). Thirty-eight patients were treated over a course of 7 weeks. Initially (day 1 + 2) patients received s.c. IL-2 at 18 x 10(6) IU m-2. During the following 6 weeks, patients received s.c. IL-2 at 3.6 x 10(6) IU m-2 for 5 days per week and s.c. INF-alpha at 5 x 10(6) for 3 days per week. Thirty-eight patients were evaluated for response. An objective response was seen in seven patients (18.4 +/- 12.3%), with one complete response and six partial responses. Median duration of response was 6.7 months. Toxicity could be evaluated in 38 patients and was limited. Mild to moderate toxicity included fever (97%), fatigue or malaise (76%), nausea or vomiting (50%), anorexia (32%), hypotension (26%), neurological disturbances (26%) and hypercreatininaemia (39%). In addition, four grade IV haematological toxicities were noted. No cardiac side-effects were seen. IL-2 and INF-alpha given by this schedule can be safely administered in an outpatient setting. The objective response rate was similar to our previous treatments with high-dose IL-2 given as a continuous infusion.


Assuntos
Carcinoma de Células Renais/terapia , Interferon Tipo I/toxicidade , Interleucina-2/toxicidade , Neoplasias Renais/terapia , Adulto , Idoso , Carcinoma de Células Renais/patologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Interferon Tipo I/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/toxicidade
18.
Oncology ; 51(1): 84-6, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8265109

RESUMO

Retinoids and interferon-alpha (IFN-alpha) have been shown to have a synergetic antiproliferative and differentiative effect on many cell lines, and in combination they have already been tested with some success in the treatment of some tumors. We investigated the tolerance and efficacy of high dose 13-cis-retinoic acid (2 mg/kg/day) and IFN-alpha in the treatment of advanced squamous cell carcinoma of the lung and of the head and neck. No partial or complete response was observed in the 10 patients treated. The toxicity was unusual and mild to moderate considering the dose of retinoid given. This observation leads us to suspect that IFN-alpha may alleviate some of the side effects of the retinoid, and is of interest in the design of future clinical trials.


Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Interferon Tipo I/toxicidade , Isotretinoína/toxicidade , Neoplasias Pulmonares/terapia , Adulto , Oftalmopatias/induzido quimicamente , Humanos , Interferon Tipo I/uso terapêutico , Isotretinoína/uso terapêutico , Pessoa de Meia-Idade , Proteínas Recombinantes , Pele/efeitos dos fármacos , Pele/patologia
19.
Urol Res ; 22(4): 247-50, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7871638

RESUMO

We investigated the activity of alpha-interferon (alpha-IFN), gamma-interferon (gamma-IFN) and tumor necrosis factor-alpha (TNF-alpha) in a panel of ten human bladder tumor cell lines. All cytokines were tested at concentrations of 100-10,000 U/ml in a clonogenic assay system. We found that alpha-IFN was active against five of the ten lines while gamma-IFN was only active against one line. TNF was active against five of the ten lines. Maximum synergisms were obtained between the alpha-IFN and TNF, occurring in nine of the ten cell lines. We conclude that alpha-IFN and TNF are active as single agents and synergistic when used together in vitro in human bladder tumor cell lines.


Assuntos
Interferon Tipo I/toxicidade , Interferon gama/toxicidade , Fator de Necrose Tumoral alfa/toxicidade , Bexiga Urinária/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Fatores Imunológicos , Proteínas Recombinantes , Células Tumorais Cultivadas , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária
20.
Neuropharmacology ; 32(12): 1433-6, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8152533

RESUMO

Immediately after recovery from hexobarbital anesthesia, mice were injected intraperitoneally with one of the following interferons: natural mouse alpha/beta, recombinant mouse (rmouse gamma IFN-A) or human alpha A, alpha D, alpha AD interferon (rHu alpha IFN-A, rHu alpha IFN-D, rHu alpha IFN-AD). All of these interferons, except rHu alpha IFN-A induced unconsciousness ("sleep"); all produced stimulatory effects that mimicked those produced by morphine in the mouse. Quantification of the duration of sleep, induced by rmouse gamma IFN, was investigated and found to be dose-related. Only 3 of the 5 interferons (mouse alpha/beta IFN; rmouse gamma IFN, rHu alpha IFN-AD) possesses antiviral activity and depresses the cytochrome P-450 system in the mouse, yet all 5 of the interferons produced CNS effects. This partition of effects, together with the very short latency of the interferon-induced CNS effects, shows that the CNS effects were mechanistically independent of the anti-viral and anti-cytochrome P-450 effects. This disparity of the actions of the interferons suggests the possibility that selected morphine antagonists could be used to counter some of the dose-limiting CNS effects of the large doses of interferons used in clinical situations.


Assuntos
Anestesia Geral , Hexobarbital , Interferon Tipo I/farmacologia , Interferon gama/farmacologia , Atividade Motora/efeitos dos fármacos , Sono/fisiologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Humanos , Interferon Tipo I/toxicidade , Interferon gama/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes , Convulsões/induzido quimicamente , Sono/efeitos dos fármacos , Relação Estrutura-Atividade
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