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1.
Int J Mol Sci ; 25(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38732169

RESUMO

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.


Assuntos
Células Dendríticas , Encefalomielite Autoimune Experimental , Vírus Elevador do Lactato Desidrogenase , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito , Animais , Feminino , Camundongos , Apresentação de Antígeno/imunologia , Infecções por Cardiovirus/imunologia , Antígeno CD11b/metabolismo , Antígeno CD11b/imunologia , Antígeno CD11c/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/virologia , Vírus Elevador do Lactato Desidrogenase/imunologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/virologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Toxicol Mech Methods ; 34(4): 385-397, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38083807

RESUMO

Polymeric poly (lactic-co-glycolic acid) (PLGA)-lipid hybrid nanoparticles (PNPs)-based therapy are powerful carriers for various therapeutic agents. This study was conducted to evaluate the chemotherapeutic potential of free 5-flurouracil (5FU) and synthetized 5FU-PNPs and impact on p53-dependent apoptosis in mammary carcinomas (MCs) grown in mice. Breast cancer cells were injected in Swiss albino female mice and 2 bilateral masses of MC were confirmed after one week. Mice were distributed to five experimental groups; Group 1: MC control group. Groups 2 and 3: MC + free 5FU [5 or 10 mg per kg] groups. Groups 4 and 5: synthetized MC+ 5FU-PNPs [5 or 10 mg per kg] groups. Medications were administered orally, twice weekly for 3 weeks. Then, tumors were dissected, and sections were stained with hematoxylin-eosin (HE) while the other MC was used for measuring of cell death and inflammatory markers. Treatment with 5FU-PNPs suppressed the MC masses and pathologic scores based on HE-staining. Similarly, greater proapoptotic activity was recorded in 5FU-PNPs groups compared to free 5FU groups as shown by significant upregulation in tumoral p53 immunostaining. The current results encourage the utility of PNPs for improving the antitumor effect of 5FU. The chemotherapeutic potential was mediated through enhancement of tumoral p53-mediated p53 up-regulated modulator of apoptosis (PUMA) genes. Additional studies are warranted for testing the antitumor activity of this preparation in other mouse models of breast cancer.

3.
Eur J Immunol ; 51(6): 1482-1493, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33788263

RESUMO

The dimeric cytokine IL-12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL-23 and p35 in IL-35. This has led to erroneous conclusions like the alleged implication of IL-12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti-mouse IL-12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL-35) but specifically recognize and functionally inhibit the IL-12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN-γ production and LPS-induced septic shock after viral infection, we demonstrate the critical role played by IL-12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG-induced EAE, which was clearly prevented by anti-p40 mAb C17.8. Given this selective inhibition of IL-12, these mAbs provide new options for reassessing IL-12 function in vivo.


Assuntos
Anticorpos Monoclonais/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Rejeição de Enxerto/imunologia , Interleucina-12/metabolismo , Mastocitoma/imunologia , Esclerose Múltipla/imunologia , Infecções por Nidovirales/imunologia , Nidovirales/fisiologia , Subunidades Proteicas/metabolismo , Sepse/imunologia , Transplante de Pele , Animais , Anticorpos Monoclonais/isolamento & purificação , Modelos Animais de Doenças , Epitopos , Humanos , Hibridomas , Interleucina-12/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neoplasias Experimentais , Subunidades Proteicas/imunologia
4.
Liver Int ; 34(6): 890-5, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24102823

RESUMO

BACKGROUND: A strong association between single nucleotide polymorphisms (SNPs) of IL28B and treatment outcomes of pegylated interferon-α (PEG IFNα) and ribavirin (RBV) has been shown in chronic hepatitis C (CHC) patients with genotype 1. AIM: This study aimed to assess two SNPs of IL28B, rs12979860 and rs8099917, in predicting sustained virological responses (SVR) to treatment of CHC patients with genotype 4 (HCV-4). The value of rs8099917 was investigated in carriers of unfavourable genotypes of rs12979860. METHODS: This study included 119 CHC patients with HCV-4 receiving combination therapy. Both SNPs of IL28B were determined by real-time detection polymerase chain reaction. RESULTS: Genotypes CC/CT/TT of rs12979860 were found in 42 (35.3%), 56 (47.1%) and 21 (17.6%) and rs8099917 TT/TG/GG were found in 74 (62.2%), 40 (33.6%) and 5 (4.2%). In carriers of rs12979860 CC and rs8099917 TT, the rate of SVR was 87.5 and 65.7% respectively. In 54 patients heterozygous for the C allele of rs12979860, testing of rs8099917 revealed SVR in 42.3% of carriers of the TT genotype but no such responses in carriers of TG or GG (P < 0.0001, OR = 47.3, 95% CI: 2.33-767.2). By multivariate analysis, predictors of SVR were baseline ALT (P = 0.014, OR = 6.3, 95% CI: 1.45-27.33), rs12979860 CC (P = 0.001, OR = 13.48, 95% CI: 2.95-61.69) and rs8099917 TT (P = 0.027, OR = 7.5, 95% CI: 1.25-44.88). CONCLUSION: In CHC genotype 4 patients, favourable genotypes of both SNPs of IL28B are valuable for predicting SVR. Additional genotyping of rs8099917 in carriers of the heterozygous C allele of rs12979860 can improve the prediction of SVR.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Ribavirina/uso terapêutico , Adulto , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Quimioterapia Combinada , Feminino , Frequência do Gene , Genótipo , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Heterozigoto , Humanos , Interferon alfa-2 , Interferons , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Seleção de Pacientes , Farmacogenética , Fenótipo , Medicina de Precisão , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto Jovem
5.
Front Med (Lausanne) ; 9: 1057252, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36714124

RESUMO

Introduction: Natural prevention of cancer development depends on an efficient immunosurveillance that may be modulated by environmental factors, including infections. Innate lymphoid cytotoxic cells have been shown to play a major role in this immunosurveillance. Interleukin-12 (IL-12) has been suggested to be a key factor in the activation of innate cytotoxic cells after infection, leading to the enhancement of cancer immunosurveillance. Methods: The aim of this work was to analyze in mouse experimental models by which mechanisms the interaction between infectious agent molecules and the early innate responses could enhance early inhibition of cancer growth and especially to assess the role of IL-12 by using novel antibodies specific for IL-12 heterodimers. Results: Ligation of toll-like receptor (TLR)9 by CpG-protected mice against plasmacytoma TEPC.1033.C2 cell early growth. This protection mediated by innate cytolytic cells was strictly dependent on IL-12 and partly on gamma-interferon. Moreover, the protective effect of CpG stimulation, and to a lesser extent of TLR3 and TLR7/8, and the role of IL-12 in this protection were confirmed in a model of early mesothelioma AB1 cell growth. Discussion: These results suggest that modulation of the mouse immune microenvironment by ligation of innate receptors deeply modifies the efficiency of cancer immunosurveillance through the secretion of IL-12, which may at least partly explain the inhibitory effect of previous infections on the prevalence of some cancers.

6.
Immunol Lett ; 217: 25-30, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726186

RESUMO

In a previous work we demonstrated that inhibition of mouse indoleamine 2,3-dioxygenase (IDO) by methyltryptophan (MT) exacerbated the pathological actions of mouse hepatitis virus (MHV-A59) infection, suggesting that tryptophan (TRP) catabolism was involved in viral effects. Since there is a second enzyme that dioxygenates TRP, tryptophan-2, 3-dioxygenase (TDO), which is mainly located in liver, we decided to study its role in our model of MHV-infection. Results showed that in vivo TDO inhibition by LM10, a derivative of 3-(2-(pyridyl) ethenyl) indole, resulted in a decrease of anti- MHV Ab titers induced by the virus infection. Besides, a reduction of some alarmin release, i.e, uric acid and high-mobility group box1 protein (HMGB1), was observed. Accordingly, since alarmin liberation was related to the expression of autoantibodies (autoAb) to fumarylacetoacetate hydrolase (FAH), these autoAb also diminished. Moreover, PCR results indicated that TDO inhibition did not abolish viral replication. Furthermore, histological liver examination did not reveal strong pathologies, whereas mouse survival was hundred percent in control as well as in MHV-infected mice treated with LM10. Data presented in this work indicate that in spite of the various TDO actions already described, specific TDO blockage could also restrain some MHV actions, mainly suppressing autoimmune reactions. Such results should prompt further experiments with various viruses to confirm the possible use of a TDO inhibitor such as LM-10 to treat either viral infections or even autoimmune diseases triggered by a viral infection.


Assuntos
Doenças Autoimunes/enzimologia , Autoimunidade/efeitos dos fármacos , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Fígado/enzimologia , Vírus da Hepatite Murina/imunologia , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/metabolismo , Alarminas/metabolismo , Animais , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Hidrolases/imunologia , Indóis/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/crescimento & desenvolvimento , Triptofano/metabolismo , Triptofano Oxigenase/genética , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
7.
Infect Agent Cancer ; 15: 30, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32391074

RESUMO

BACKGROUND: Viral infections can reduce early cancer development through enhancement of cancer immunosurveillance. This study was performed to analyse this effect of viral infection in a mouse model of solid tumor. METHODS: The experimental model used was the effect of BALB/c mouse infection by lactate dehydrogenase-elevating virus on AB1 mesothelioma cancer development. RESULTS: Acute infection with lactate dehydrogenase-elevating virus strongly reduced in vivo early AB1 mesothelioma growth and death resulting from cancer development. This effect was not due to a direct cytolytic effect of the virus on AB1 cells, but to an in vivo activation of natural killer cells. Gamma-interferon production rather than cytotoxic activity against AB1 cells mediated this protective effect. This gamma-interferon production by natural killer cells was dependent on interleukin-12 production. CONCLUSIONS: Together with other reported effects of infectious agents on cancer development, this observation may support the hypothesis that enhancement of innate immunosurveillance against tumors may result from infection with common infectious agents through modulation of the host immune microenvironment.

8.
Pharmacol Rep ; 67(1): 102-14, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25560583

RESUMO

BACKGROUND: Safety of the combination of leflunomide and methotrexate was examined in several studies with inconclusive results. The present study was designed to compare the efficacy and safety of the combination of leflunomide and methotrexate in adjuvant-induced arthritis (AIA) in rats focusing on immunosuppressive and hepatotoxic effects. METHODS: Eighty four rats were divided into seven groups. Group 1: Sham control, group 2: the vehicle control, group 3: methotrexate group, group 4-5: leflunomide (5 and 10mg/kg/day) groups, group 6-7: combination 1 and 2 [methotrexate+leflunomide (5 and 10mg/kg/day)] groups, respectively. RESULTS: The current results indicated that combination therapies improved the ankle circumference and clinical scores compared to monotherapies; histopathological examination confirmed these findings. The myelosuppressive effect of leflunomide (10mg/kg/day) was comparable to that produced by methotrexate as indicated by the complete blood count and bone marrow cellularity; however their combination resulted in greater toxicity. Furthermore, methotrexate greatly affected the splenic histopathology compared to leflunomide and the combination therapy produced a greater effect compared to leflunomide not methotrexate. Differently, assessment of the hepatotoxic potential of the two drugs highlighted that leflunomide induced a dose-dependent increase in the fibrosis score which was higher in their magnitude than that induced by methotrexate. Leflunomide (10mg/kg/day) and combination 2 groups showed the greatest degree of liver fibrosis. CONCLUSIONS: In rats with AIA, current drug combinations provided higher therapeutic benefit compared to monotherapies, however, greater toxicities were observed. Therefore, continuous monitoring of hematologic parameters and liver function will be recommended in clinical settings.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/toxicidade , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Doenças da Medula Óssea/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Isoxazóis/toxicidade , Isoxazóis/uso terapêutico , Metotrexato/toxicidade , Metotrexato/uso terapêutico , Animais , Contagem de Células Sanguíneas , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Doenças da Medula Óssea/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Medicamentosas , Membro Posterior/patologia , Leflunomida , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Wistar , Baço/patologia
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