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1.
Rev Soc Bras Med Trop ; 53: e20200152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578715

RESUMO

During the yellow fever (YF) outbreak in Brazil, many cases of fulminant hepatitis were seen, although mild to moderate hepatitis was mostly observed with complete recovery. This report presents a case of late-onset hepatitis due to YF relapse. The patient sought medical attention after jaundice recurrence 40 days after the first YF hepatitis episode. This case highlights the importance of patient follow-up after the complete resolution of YF symptoms and discharge.


Assuntos
Hepatite/complicações , Febre Amarela/complicações , Adulto , Hepatite/imunologia , Humanos , Masculino , Recidiva
2.
Gastroenterology ; 157(4): e8-e9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476298
3.
Int Immunopharmacol ; 75: 105808, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419710

RESUMO

AIMS: Immune mediated liver injury includes activation of different immune pathways that requires various modalities to control their consequences. The current study involves evaluation of retinoic acid (RA) modulatory effects on immune responses induced in concanavalin A (ConA) model of acute hepatitis. MAIN METHODS: Mice were divided as follows: Control group; RA group: received 35 mg/kg RA; ConA group: received 15 mg/kg ConA; ConA + RA group: received ConA and RA as described. Liver function biomarkers were measured in addition to malondialdehyde as lipid peroxidation biomarker. Liver tissue sections were scored for necro-inflammation, neutrophils infiltration, CD4+ T cells infiltration and NF-κb positive cells. Effect on hepatic levels of TNF-α, IL-4, IL-10 and MCP-1 was evaluated as well. KEY FINDINGS: Injection of RA before ConA significantly (p < 0.001) decreased ALT, AST and LDH levels compared to their levels in ConA group. Hepatic infiltration of neutrophils and CD4+ T cells was markedly (p < 0.001) reduced by RA. Hepatic injury, necrosis and expression of NF-κb were significantly decreased by RA when injected before ConA challenge. A significant decrease in the measured cytokines TNF-α and IL-4 was observed in ConA + RA group in addition to a decrease in MCP-1 level. On the other hand, IL-10 was significantly increased in the latter group compared to ConA group. SIGNIFICANCE: RA can protect against ConA-induced hepatitis through: interrupting early inflammatory response as neutrophils, monocytes and CD4+ T cells infiltration, modulating IL-4 level and subsequent production of TNF-α and NF-κb activation, mitigating second inflammatory responses through increasing IL-10 liver production.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocinas/imunologia , Hepatite/imunologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A , Hepatite/patologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Transdução de Sinais/efeitos dos fármacos
4.
Sci Immunol ; 4(36)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253642

RESUMO

The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how elevated blood pressure initiates inflammation is unknown, as are the effects of high blood pressure on innate and adaptive immune responses. We now report that hypertensive mice have increased T cell responses to antigenic challenge and develop more severe T cell-mediated immunopathology. A root cause for this is hypertension-induced erythrocyte adenosine 5'-triphosphate (ATP) release, leading to an increase in plasma ATP levels, which begins soon after the onset of hypertension and stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. Hydrolyzing ATP or blocking the P2X7 receptor eliminated hypertension-induced T cell hyperactivation. In addition, pharmacologic or genetic blockade of P2X7 receptor activity suppressed the progression of hypertension. Consistent with the results in mice, we also found that untreated human hypertensive patients have significantly elevated plasma ATP levels compared with treated hypertensive patients or normotensive controls. Thus, a hypertension-induced increase in extracellular ATP triggers augmented APC and T cell function and contributes to the immune-mediated pathologic changes associated with hypertensive disease.


Assuntos
Trifosfato de Adenosina/imunologia , Hipertensão/imunologia , Trifosfato de Adenosina/sangue , Adulto , Idoso , Animais , Antígenos/imunologia , Antígeno B7-2/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Hepatite/imunologia , Humanos , Hipertensão/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Ovalbumina/imunologia , Receptores Purinérgicos P2X7/genética , Linfócitos T/imunologia
5.
PLoS Negl Trop Dis ; 13(6): e0007474, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194740

RESUMO

During Schistosoma infection, lack of B cells results in more severe granulomas, inflammation, and fibrosis in the liver, but the mechanisms underlying this pathology remain unclear. This study was to clarify the mechanisms underpinning the immunomodulation of B cells in mice infected with Schistosoma japonicum (S. japonicum). We found that B cell deficiency led to aggravated liver pathology, as demonstrated by increases in the size of the egg-associated granulomas, alanine transaminase levels, and collagen deposition. Compared with infected wild-type (WT) mice, infected B cell-deficient (µMT) mice showed increased infiltration of Ly6Chi monocytes and higher levels of proinflammatory cytokines and chemokines. Furthermore, B1 cells were increased significantly in the liver of WT mice following S. japonicum infection. Adoptively transferring B1 cells, but not B2 cells, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. Additionally, secretion of IL-10 from hepatic B cells increased significantly in infected WT mice and this IL-10 was mainly derived from B1 cells. Adoptively transferring B1 cells purified from WT mice, but not from IL-10-deficient mice, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. These reductions were accompanied by decreases in the expression levels of chemokines and inflammatory cytokines. Taken together, these data indicated that after S. japonicum infection, an increased number of hepatic B1 cells secrete IL-10, which inhibits the expression of chemokines and cytokines and suppresses the infiltration of Ly6Chi monocytes into the liver thereby alleviating liver early inflammation and late fibrosis.


Assuntos
Linfócitos B/imunologia , Hepatite/complicações , Hepatite/prevenção & controle , Cirrose Hepática/prevenção & controle , Monócitos/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/complicações , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite/imunologia , Fatores Imunológicos/metabolismo , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL
6.
Dig Dis Sci ; 64(10): 2867-2877, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31049763

RESUMO

BACKGROUND: Probiotic use to prevent gastrointestinal infections in critical care has shown great promise in recent clinical trials. Although well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to ameliorate liver injury and hypoxic hepatitis following sepsis has not been well explored. METHODS: In order to evaluate, if Lactobacillus rhamnosus GG (LGG) treatment in septic rats will protect against liver injury, this study used 20-22-week-old Sprague-Dawley rats which were subjected to cecal ligation and puncture to establish sepsis model and examine mRNA and protein levels of IL-1ß, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α in the liver via real-time PCR, Elisa and Western blot. RESULTS: This study showed that LGG treatment significantly ameliorated liver injury following experimental infection and sepsis. Liver mRNA and protein levels of IL-1ß, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α were significantly reduced in rats receiving LGG. CONCLUSIONS: Thus, our study demonstrated that LGG treatment can reduce liver injury following experimental infection and sepsis and is associated with improved hypoxic hepatitis. Probiotic therapy may be a promising intervention to ameliorate clinical liver injury and hypoxic hepatitis following systemic infection and sepsis.


Assuntos
Hepatite , Lactobacillus rhamnosus , Falência Hepática , Probióticos/farmacologia , Sepse , Animais , Hepatite/etiologia , Hepatite/imunologia , Hepatite/prevenção & controle , Interleucina-1beta/metabolismo , Fígado/metabolismo , Fígado/patologia , Falência Hepática/etiologia , Falência Hepática/imunologia , Falência Hepática/prevenção & controle , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/terapia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
8.
Transplant Proc ; 51(4): 1193-1195, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981408

RESUMO

Infections after solid organ transplantation are a major cause of mortality and morbidity. Varicella-zoster virus (VZV) infection after solid organ transplantation is rare. Here we present a case presenting with acute hepatitis and shingles after a liver transplantation (LT). A 36-year-old male patient underwent a liver transplantation; 7 months later his liver function tests increased. An examination and test results revealed that he had VZV-induced hepatitis. After VZV treatment, his test results returned to normal levels. Hepatic involvement of VZV infection is rare, but it may be fatal in immunocompromised individuals. Early diagnosis and early initiation of antiviral therapy is important in the control of hepatitis and rare hepatotropic viruses in immunocompromised individuals.


Assuntos
Hepatite/imunologia , Herpes Zoster/imunologia , Hospedeiro Imunocomprometido , Transplante de Fígado/efeitos adversos , Adulto , Herpesvirus Humano 3 , Humanos , Masculino
9.
Biomed Pharmacother ; 112: 108638, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784928

RESUMO

Vindoline, an indole alkaloid present in the leaves of Catharanthus roseus plant, has been recently reported to have insulotropic effects. This present study evaluated the possible hepatoprotective effects of vindoline in a type 2 diabetes mellitus rat model. Diabetes mellitus was induced by exposing rats to 10% fructose water for two weeks followed by a single intraperitoneal injection of 40 mg/kg body weight of streptozotocin (STZ). Rats were randomly divided into six groups (n = 8) and treated daily for 6 weeks with the vehicle via oral gavage, vindoline (20 mg/kg) or glibenclamide (5 mg/kg). Weekly fasting blood glucose (FBG) levels and body weight were measured and recorded. Administration of vindoline significantly (p < 0.05) reduced FBG by 15% when compared to the diabetic controls. Vindoline significantly (p < 0.05) decreased diabetes-induced hepatic injury shown by decreased levels of serum alanine transferase (ALT) (-42%), aspartate aminotransferase (AST) (-42%) and alkaline phosphatase (-62%) compared to the diabetic controls. The oxygen radical absorbance capacity and the activities of superoxide dismutase (SOD) and catalase (CAT) were also improved following treatment with vindoline. The results also showed decreased levels of pro-inflammatory cytokines such as TNF-ɑ by (-41%) and IL-6 (-28%) which may have also contributed to the reduction of serum triglycerides (-65%) in the diabetic group treated with vindoline. Histopathological findings showed improvement of both the hepatic and pancreatic tissues following vindoline treatment. Overall, these findings suggest that vindoline may protect the diabetic hepatic tissue from injury via antioxidant, anti-inflammatory and anti-hypertriglyceredemia mechanisms thereby retarding the development of diabetic complications.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hepatite/prevenção & controle , Hipertrigliceridemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Vimblastina/análogos & derivados , Animais , Glicemia/análise , Catharanthus/química , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glibureto/uso terapêutico , Hepatite/imunologia , Hepatite/metabolismo , Hepatite/patologia , Insulina/sangue , Testes de Função Hepática , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos Wistar , Vimblastina/uso terapêutico
10.
Cell Mol Gastroenterol Hepatol ; 7(3): 623-639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30630119

RESUMO

BACKGROUND & AIMS: Chemokine-mediated immune cell recruitment plays pivotal roles in liver inflammation. C-C motif chemokine ligand 5 (CCL5) has been shown to be responsible for the recruitment of monocytes/macrophages and has been implicated in various liver diseases, including nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma. Previous studies have also shown that inhibition of CCL5 appears to be a promising therapeutic approach for several chronic liver diseases. However, whether blocking CCL5 could benefit immune cell-mediated hepatitis remains largely elusive. METHODS: By adopting a specific agonist, alpha-galactosylceramide (α-Galcer), of invariant natural killer T cells (iNKTs), we investigated the function and mechanism of CCL5 in the iNKT induced murine hepatitis model. RESULTS: We found significantly increased CCL5 expression in α-Galcer-induced hepatitis murine model. Such an increase in CCL5 is mainly enriched in non-parenchymal cells such as macrophages and iNKTs but not in hepatocytes. Surprisingly, CCL5 blockage by genetic deletion of Ccl5 does not affect the α-Galcer-induced iNKT activation but greatly worsens α-Galcer-induced liver injury accompanied by an increased hepatic neutrophil infiltration. Mechanistically, we demonstrated that greater neutrophil accumulation in the liver is responsible for the enhanced liver injury in Ccl5-/- mice. Such an increased hepatic neutrophil infiltration is mainly caused by an enhanced CXCL1-CXCR2 signal in Ccl5-/- mice. Therapeutically, either antibody-mediated neutrophil depletion or a CXCR2 antagonist, SB225002, mediated CXCR2 signaling blockage significantly ameliorated α-Galcer-induced liver injury in Ccl5-/- mice. CONCLUSIONS: Our present study demonstrates that (1) α-Galcer-induced murine hepatitis could greatly induce CCL5 production in macrophages and iNKT cells; (2) loss of CCL5 could enhance CXCL1 expression in hepatocytes and activate CXCL1-CXCR2 axis in neutrophils to augment their hepatic infiltration; and (3) neutrophil depletion or blockage of CXCL1-CXCR2 axis greatly improves α-Galcer-induced liver injury in Ccl5-/- mice. This study suggests that clinical utilization of CCL5 blockage may compensatorily induce the activation of other chemokine pathways to enhance neutrophil recruitment and liver injury in hepatitis.


Assuntos
Quimiocina CCL5/deficiência , Deleção de Genes , Hepatite/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Interleucina-8B/genética , Regulação para Cima , Adulto , Idoso , Animais , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Galactosilceramidas/administração & dosagem , Hepatite/sangue , Hepatite/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Neutrófilos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina-8B/metabolismo , Baço/metabolismo , Adulto Jovem
11.
Arthritis Rheumatol ; 71(1): 161-168, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30073799

RESUMO

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome that occurs in patients with underlying rheumatic diseases. Preclinical and clinical data suggest that interferon-γ (IFNγ) is pathogenic in MAS, but how IFNγ may be linked to disease pathogenesis remains unknown. This study was undertaken to determine whether IFNγ signals synergize with systemic innate immune responses to drive the cytokine storm in a murine model of MAS. METHODS: IFNγ-deficient mice were treated with 5 doses of the Toll-like receptor 9 (TLR-9) agonist CpG 1826, IFNγ, or a combination of the 2 stimuli over the course of 10 days. Immunopathologic features of MAS, including cytopenias, hepatitis, hepatosplenomegaly, and induction of inflammatory myelopoiesis, were assessed. Mixed bone marrow chimeras were created to determine whether TLR-9- and IFNγ receptor 1 (IFNγR1)-dependent signals induce enhanced myelopoiesis in a cell-intrinsic or cell-extrinsic manner. RESULTS: IFNγ-deficient mice did not develop features of MAS when treated with repeated doses of either the TLR-9 agonist or IFNγ alone. In contrast, IFNγ-deficient mice treated with both the TLR-9 agonist and IFNγ developed cytopenias, hepatitis, and hepatosplenomegaly, reproducing major clinical features of MAS. TLR-9- and IFNγR1-dependent signals synergized to enhance myeloid progenitor cell function and induce myelopoiesis in vivo, which occurred through cell-extrinsic mechanisms and correlated with the induction of disease. CONCLUSION: These findings demonstrate that TLR-9-driven signals potentiate the effects of IFNγ to initiate murine MAS, and provide evidence that induction of inflammatory myelopoiesis is a common TLR-9- and IFNγ-dependent pathway that may contribute to the pathogenesis of MAS.


Assuntos
Interferon gama/imunologia , Síndrome de Ativação Macrofágica/imunologia , Mielopoese/efeitos dos fármacos , Receptor Toll-Like 9/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Hepatite/imunologia , Hepatomegalia/imunologia , Interferon gama/farmacologia , Fígado/efeitos dos fármacos , Camundongos , Oligodesoxirribonucleotídeos/farmacologia , Receptores de Interferon/imunologia , Baço/efeitos dos fármacos , Esplenomegalia/imunologia , Receptor Toll-Like 9/agonistas , Quimeras de Transplante
12.
Infect Dis Health ; 24(1): 13-22, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30541695

RESUMO

BACKGROUND: Immunocompromised travelers (ICTs) are medically complex and challenging for travel medicine providers. Our study hypothesizes that ICTs have high-risk travel itineraries and do not have adequate immunity against vaccine-preventable infections. METHODS: This retrospective review of 321 ICTs from 2004 to 2015 included patients with solid organ transplant (SOT, n = 134), connective tissue disease (CTD, n = 121), inflammatory bowel disease (IBD, n = 46), and human immunodeficiency virus (HIV, n = 20). Variables included immunosuppressive medications, hepatitis A and B vaccination and serology, gamma-globulin use, and antimalarial and antidiarrheal prophylaxis. Chi-square analysis was used for categorical variables and Kruskal-Wallis for continuous variables. RESULTS: Malaria-endemic regions accounted for 38.9% (125/321) of travel destinations. High-risk activities were planned by 37.4% (120/321) of travelers. A significant proportion of HIV patients [70.0% (14/20)] visited friends and relatives, whereas other ICTs traveled for tourism. Hepatitis A and B vaccination rates were 77.3% (248/321) and 72.3% (232/321). Post-vaccination hepatitis A and B serologic testing were completed by 66.1% (41/62) and 61.1% (11/18) of travelers, respectively. CONCLUSION: ICTs demonstrate differences in travel patterns and risk. Serologic testing was uncommon, and vaccination rates were low. Providers should screen ICTs early for upcoming travel plans and advise vaccine completion prior to departure.


Assuntos
Hospedeiro Imunocomprometido , Viagem , Adulto , Idoso , Antidiarreicos/administração & dosagem , Antimaláricos/administração & dosagem , Feminino , Infecções por HIV/imunologia , Hepatite/imunologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Vacinação , Vacinas contra Hepatite Viral/administração & dosagem
13.
Sci Rep ; 8(1): 16238, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389969

RESUMO

Multi drug resistance protein 2 knockout mice (Mdr2-/-) are a mouse model of chronic liver inflammation and inflammation-induced tumour development. Here we investigated the kinetics of early heme oxygenase 1 (HO-1) induction on inflammation, tumour development, and DNA damage in Mdr2-/- mice. HO-1 was induced by intraperitoneal injection of cobalt protoporphyrin IX (CoPP) twice weekly for 9 consecutive weeks. Immediately after HO-1 induction, liver function improved and infiltration of CD4+ and CD8+ T cells was reduced. Furthermore, we observed increased p38 activation with concomitant reduction of Cyclin D1 expression in aged Mdr2-/- mice. Long-term effects of HO-1 induction included increased CD8+ T cell infiltration as well as delayed and reduced tumour growth in one-year-old animals. Unexpectedly, DNA double-strand breaks were detected predominantly in macrophages of 65-week-old Mdr2-/- mice, while DNA damage was reduced in response to early HO-1 induction in vivo and in vitro. Overall, early induction of HO-1 in Mdr2-/- mice had a beneficial short-term effect on liver function and reduced hepatic T cell accumulation. Long-term effects of early HO-1 induction were increased CD8+ T cell numbers, decreased proliferation as wells as reduced DNA damage in liver macrophages of aged animals, accompanied by delayed and reduced tumour growth.


Assuntos
Reparo do DNA/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Heme Oxigenase-1/metabolismo , Hepatite/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Proteínas de Membrana/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Dano ao DNA , Modelos Animais de Doenças , Feminino , Hepatite/genética , Hepatite/imunologia , Hepatite/patologia , Humanos , Injeções Intraperitoneais , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , Protoporfirinas/administração & dosagem
14.
PLoS One ; 13(11): e0200432, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30462657

RESUMO

The significance of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.


Assuntos
Hepatite/imunologia , Macrófagos do Fígado/imunologia , Proteína 1 Modificadora da Atividade de Receptores/imunologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Células Cultivadas , Concanavalina A/imunologia , Citocinas/imunologia , Deleção de Genes , Hepatite/genética , Hepatite/patologia , Imunidade Inata , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 1 Modificadora da Atividade de Receptores/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
15.
Cell Rep ; 25(1): 68-79.e4, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30282039

RESUMO

Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8+ T cells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36 days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8+ T cell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Fígado/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Epitopos , Hepatite/imunologia , Interleucina-15/imunologia , Fígado/citologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
J Immunol Res ; 2018: 6328713, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30151394

RESUMO

Differences in LPS responsiveness influence the outcome of patients with sepsis. The intensity of the response is highly variable in patients and strain dependent in rodents. However, the role of the liver for initiating the LPS response remains ill defined. We hypothesize that hepatic LPS uptake is a key event for initiating the LPS response. In the present study, the severity of the LPS-induced inflammatory response and the hepatic LPS uptake was compared in two rat strains (Lewis (LEW) rats and Brown Norway (BN) rats). Using a transplantation model, we demonstrated the decisive role of the liver. The expression of hepatic TNF-α, IL-6, and IL-1ß mRNA levels in BN rats was significantly lower than that in LEW rats. LEW rats were sensitized to LPS via G-CSF pretreatment. Sensitization caused by G-CSF pretreatment induced severe liver injury and mortality in LEW rats, but not in BN rats (survival rate: 0% (LEW) versus 100% (BN), p < 0.01). LEW rats presented with higher liver enzymes, more alterations in histology, and higher expression of caspase 3 and higher cytokines levels. One of the reasons could be the increased hepatic LPS uptake, which was only observed in LEW but not in BN livers. Using the transplantation model revealed the decisive role of the LPS responsiveness of the liver. Injection of LPS to the high-responding LEW recipient before transplantation of a low-responder BN liver resulted in a 50% survival rate. In contrast, injecting the same dose of LPS into the high-responding LEW recipient after transplanting the low-responding BN liver resulted in a 100% survival rate. The severity of inflammatory response in different strains might be related to the differences in hepatic LPS uptake. This observation suggests that the liver plays a genetically defined decisive role in modulating the inflammatory severity.


Assuntos
Hepatite Animal/imunologia , Hepatite/imunologia , Transplante de Fígado , Fígado/imunologia , Sepse/imunologia , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fator Estimulador de Colônias de Granulócitos/imunologia , Hepatite/genética , Hepatite Animal/genética , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Sepse/genética , Transcriptoma
18.
J Virol ; 92(21)2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30111571

RESUMO

Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important but incompletely understood pathogen causing high mortality during pregnancy and leading to chronic hepatitis in immunocompromised individuals. The underlying mechanisms leading to hepatic damage remain unknown; however, the humoral immune response is implicated. In this study, immunoglobulin (Ig) heavy chain JH -/- knockout gnotobiotic pigs were generated using CRISPR/Cas9 technology to deplete the B-lymphocyte population, resulting in an inability to generate a humoral immune response to genotype 3 HEV infection. Compared to wild-type gnotobiotic piglets, the frequencies of B lymphocytes in the Ig heavy chain JH -/- knockouts were significantly lower, despite similar levels of other innate and adaptive T-lymphocyte cell populations. The dynamic of acute HEV infection was subsequently determined in heavy chain JH -/- knockout and wild-type gnotobiotic pigs. The data showed that wild-type piglets had higher viral RNA loads in feces and sera compared to the JH -/- knockout pigs, suggesting that the Ig heavy chain JH -/- knockout in pigs actually decreased the level of HEV replication. Both HEV-infected wild-type and JH -/- knockout gnotobiotic piglets developed more pronounced lymphoplasmacytic hepatitis and hepatocellular necrosis lesions than other studies with conventional pigs. The HEV-infected JH -/- knockout pigs also had significantly enlarged livers both grossly and as a ratio of liver/body weight compared to phosphate-buffered saline-inoculated groups. This novel gnotobiotic pig model will aid in future studies into HEV pathogenicity, an aspect which has thus far been difficult to reproduce in the available animal model systems.IMPORTANCE According to the World Health Organization, approximately 20 million HEV infections occur annually, resulting in 3.3 million cases of hepatitis E and >44,000 deaths. The lack of an efficient animal model that can mimic the full-spectrum of infection outcomes hinders our ability to delineate the mechanism of HEV pathogenesis. Here, we successfully generated immunoglobulin heavy chain JH -/- knockout gnotobiotic pigs using CRISPR/Cas9 technology, established a novel JH -/- knockout and wild-type gnotobiotic pig model for HEV, and systematically determined the dynamic of acute HEV infection in gnotobiotic pigs. It was demonstrated that knockout of the Ig heavy chain in pigs decreased the level of HEV replication. Infected wild-type and JH -/- knockout gnotobiotic piglets developed more pronounced HEV-specific lesions than other studies using conventional pigs, and the infected JH -/- knockout pigs had significantly enlarged livers. The availability of this novel model will facilitate future studies of HEV pathogenicity.


Assuntos
Vírus da Hepatite E/patogenicidade , Hepatite E/patologia , Hepatite/virologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias J de Imunoglobulina/genética , Fígado/patologia , Animais , Linfócitos B/citologia , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Fezes/virologia , Vida Livre de Germes , Hepatite/imunologia , Imunidade Humoral/genética , Fígado/virologia , Contagem de Linfócitos , Depleção Linfocítica , RNA Viral/genética , Suínos , Carga Viral/genética
19.
Clin Adv Hematol Oncol ; 16(5): 364-374, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29851932

RESUMO

Remarkable efficacy has been achieved in a variety of cancer types by targeting immune checkpoints. The cytotoxic T-lymphocyte-associated antigen 4 inhibitor ipilimumab, the programmed death 1 inhibitors nivolumab and pembrolizumab, and the programmed death ligand 1 inhibitors atezolizumab, avelumab, and durvalumab are the agents currently approved by the US Food and Drug Administration for the treatment of certain advanced malignancies. These agents mark a departure from both standard cytotoxic chemotherapy and targeted therapy. However, they are associated with a unique set of immune-related adverse events (irAEs), which can manifest as a wide range of autoimmune phenomena. The irAEs can affect any system in the body and in rare cases are life-threatening. It is critical for the practicing medical oncologist to recognize and promptly treat any irAEs that may develop.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Hematológicas/tratamento farmacológico , Imunoterapia/efeitos adversos , Ipilimumab/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Colite/etiologia , Colite/genética , Colite/imunologia , Colite/prevenção & controle , Dermatite/etiologia , Dermatite/genética , Dermatite/imunologia , Dermatite/prevenção & controle , Gerenciamento Clínico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Hepatite/etiologia , Hepatite/genética , Hepatite/imunologia , Hepatite/prevenção & controle , Humanos , Imunoterapia/métodos , Ipilimumab/administração & dosagem , Nivolumabe , Pneumonia/etiologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/prevenção & controle , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia
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