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1.
Vaccine ; 41(48): 7297-7306, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37925316

RESUMO

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Método Duplo-Cego , População do Leste Asiático , Imunogenicidade da Vacina , SARS-CoV-2 , Vacinas de mRNA
2.
Lancet Microbe ; 3(3): e193-e202, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35098177

RESUMO

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , China , Humanos , Imunogenicidade da Vacina , Imunoglobulina G , Pandemias/prevenção & controle , Glicoproteína da Espícula de Coronavírus , Vacinas Sintéticas , Vacinas de mRNA
3.
World J Clin Cases ; 7(19): 3090-3097, 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31624759

RESUMO

BACKGROUND: Kaposi's sarcoma (KS) is one of the most common cancers in human immunodeficiency virus (HIV)-positive patients and leads to a high prevalence of morbidity and mortality. It usually appears as cutaneous or mucous lesions. Patients with visceral KS are asymptomatic and clinically silent. As the disease advances, patients may progress from a normal condition to exhibiting severe symptoms. CASE SUMMARY: A 27-year-old man presented with a 2-mo history of fever, bearing-down pain, and rectal bleeding. His hepatitis B virus DNA level was 2.7 ×107 IU/mL. Abdominal computed tomography (CT) indicated liver cirrhosis. Before he was admitted to our hospital, he was diagnosed with HIV infection. His CD4 count was 24 cells/µL. Pelvic cavity CT suggested a thickened rectum wall accompanied by multiple enlarged lymph nodes. The patient was initially treated as having haemorrhoidal varices with bleeding, telbivudine for anti-hepatitis B virus treatment, and antibiotics for anti-infection. After half a month of treatment, the patient felt that his lower lumbus ache and bearing-down pain had not improved, and a colonoscopy was conducted. The result revealed a rectal mass that was histologically confirmed as KS with rectal spindle cells that were positive for cluster of differentiation 117 (CD117), CD34, human herpes virus 8, and CD31. He was administered systemic chemotherapy with 36 mg/d liposomal doxorubicin six times. The patient experienced no sign of lower gastrointestinal bleeding again. CONCLUSION: This case highlights the diagnosis of primary KS with lower gastrointestinal bleeding in HIV-positive patients, which means visceral KS could not be excluded. The gold standard relies on colonoscopy and biopsy findings.

4.
Clin Ther ; 35(12): 1997-2006, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24238791

RESUMO

BACKGROUND: Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients. OBJECTIVE: The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB. METHODS: A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1. RESULTS: Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group. CONCLUSIONS: For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Ensaios Clínicos como Assunto , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Guanina/uso terapêutico , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/imunologia , Humanos , Masculino , Resultado do Tratamento
5.
Mol Med Rep ; 8(1): 103-12, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23685705

RESUMO

Liver cells release the high mobility group box-1 (HMGB1) protein when exposed to lipopolysaccharides (LPSs). However, the timing and levels of protein released remain unclear. The present study aimed to characterize the secretion of the late pro-inflammatory cytokine HMGB1 by liver L02 and HepG2 cells. The human mononuclear macrophage cell line U937 was used as a control. Various concentrations of LPS were added to human U937, L02 and HepG2 cells for different durations, and the cells were analyzed at different time-points following this addition. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure cellular HMGB1 mRNA levels, western blotting was performed to detect HMGB1 in cellular supernatants and the translocation of HMGB1 from the nucleus to the cytosol was examined using immunofluorescence staining. L02 and HepG2 cells exhibited higher HMGB1 mRNA levels compared with the control U937 cells 20 and 24 h following continuous exposure to LPS. U937 cells exhibited higher HMGB1 mRNA levels compared with the corresponding L02 and HepG2 cells 16 h following LPS exposure. The phase of HMGB1 protein detected in the cellular supernatants of L02 and HepG2 cells (16 h) was later than that of U937 cells (8 h). For the three cell lines, HMGB1 levels demonstrated a time dependency; however, the protein level was the highest in U937 cells. In the three cell lines, translocation of HMGB1 from the nucleus to the cytosol occurred; however, the phases of HMGB1 translocation in L02 and HepG2 cells occurred later than in U937 cells. LPS-induced secretion of the late pro­inflammatory cytokine HMGB1 by liver cells is characterized by a late phase of release and smaller quantity, and the process of HMGB1 secretion appears to be associated with HMGB1 translocation.


Assuntos
Proteína HMGB1/biossíntese , Lipopolissacarídeos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/genética , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células U937
6.
Int J Mol Sci ; 12(6): 3846-56, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21747711

RESUMO

In this study, levels of plasma α2-Heremans-Schmid glycoprotein, serum tumor necrosis factor-α, serum liver function parameters and short-term mortality were measured in 100 hepatitis B patients. Release of interleukin-6 and tumor necrosis factor-α from the lipopolysaccharide-stimulated peripheral blood mononuclear cells in the presence/absence of spermine and α2-Heremans-Schmid glycoprotein were analyzed by enzyme-linked immunosorbent assay to determine the significance and potential mechanism of α2-Heremans-Schmid glycoprotein in hepatitis B virus-associated liver damage. Results showed that serum α2-Heremans-Schmid glycoprotein levels in acute-on-chronic liver failure patients were significantly lower than that in chronic hepatitis B patients or healthy controls (p < 0.05). A negative dependence between serum human α2-Heremans-Schmid glycoprotein and tumor necrosis factor-α levels was observed. Interleukin-6 and tumor necrosis factor-α levels in the lipopolysaccharide-induced peripheral blood mononuclear cell supernates were significantly reduced by spermine and/or α2-Heremans-Schmid glycoprotein. The latter two proteins jointly inhibited cytokine release. These observations suggest that plasma α2-Heremans-Schmid glycoprotein is an independent marker of liver damage and a prognostic indicator of hepatitis B virus chronicity. It may reduce liver inflammation by partially inhibiting release of inflammatory factors from activated peripheral blood mononuclear cells.


Assuntos
Vírus da Hepatite B/fisiologia , Falência Hepática/sangue , alfa-2-Glicoproteína-HS/análise , Adulto , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Humanos , Interleucina-6/sangue , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Falência Hepática/metabolismo , Falência Hepática/patologia , Masculino , Pessoa de Meia-Idade , Espermina/sangue , Fator de Necrose Tumoral alfa/sangue
7.
Int Immunopharmacol ; 11(8): 1018-23, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21356341

RESUMO

The release of pro-inflammatory cytokines in both acute (IL-1ß and TNF-α) and chronic [high mobility group box 1 protein (HMGB1)] phases, is thought to play important roles in the development of fulminant hepatitis (FH). Triterpenoid Acankoreanogenin A (AA) which is extracted from the leaves of the Acanthopanax gracilistylus W.W. Smith (AGS) has shown its inhibiting effect on TNF-α, IL-1ß and HMGB1 release in vitro in our preliminary experiments. In present study, we investigated the effect of AA on mice with fulminant hepatitis in vivo. Fulminant hepatitis mice model was established by intraperitoneally injecting galactosamine (GalN) and lipopolysaccharide (LPS). The levels of serum of TNF-α, IL-1ß, ALT, AST and HMGB1 from AA-treated mice were measured at different time points. Our results demonstrated that pre-treatment of mice with AA markedly reduced the serum levels of TNF-α, IL-1ß, HMGB1, ALT and AST with the improvement in histological features. And the survival rate from AA-treated fulminant hepatitis mice was increased. Furthermore, delayed administration of AA after peak occurrence of the early pro-inflammatory cytokines still endowed significant protection against GalN/LPS-induced lethality. The post-treatment of AA could significantly attenuate the release of HMGB1, but not the TNF-α and IL-1ß. These results indicate that AA inhibits the systemic release of pro-inflammatory cytokine HMGB1, and dose-dependently rescue the mice from lethal GalN/LPS-induced fulminant hepatitis, which suggests this component as a candidate therapy for fulminant hepatitis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Falência Hepática Aguda/tratamento farmacológico , Alanina Transaminase/antagonistas & inibidores , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/antagonistas & inibidores , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Eleutherococcus , Feminino , Galactosamina/farmacologia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
8.
Virol J ; 8: 111, 2011 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-21388525

RESUMO

Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients with chronic hepatitis B. tenofovir is a nucleoside analog with selective activity against hepatitis b virus and has been shown to be more potent in vitro than adefovir. But the results of trials comparing tenofovir and adefovir in the treatment of chronic hepatitis B were inconsistent. However, there was no systematic review on the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B. To evaluate the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B we conducted a systematic review and meta-analysis of clinical trials. We searched PUBMED, Web of Science, EMBASE, CNKI, VIP database, WANFANG database, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review. Finally six studies were left for analysis which involved 910 patients in total, of whom 576 were included in tenofovir groups and 334 were included in adefovir groups. At the end of 48-week treatment, tenofovir was superior to adefovir at the HBV-DNA suppression in patients[RR = 2.59; 95%CI(1.01-6.67), P = 0.05]. While there was no significant difference in the ALT normalization[RR = 1.15; 95%CI(0.96-1.37), P = 0.14], HBeAg seroconversion[RR = 1.32; 95%CI(1.00-1.75), P = 0.05] and HBsAg loss rate[RR = 1.19; 95%CI(0.74-1.91), P = 0.48]. More high-quality, well-designed, randomized controlled, multi-center trails are clearly needed to guide evolving standards of care for chronic hepatitis B.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Ensaios Clínicos Controlados como Assunto , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Humanos , Tenofovir , Resultado do Tratamento
9.
BMC Gastroenterol ; 11: 21, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21406085

RESUMO

BACKGROUND: High-mobility group box 1 (HMGB1) is a late mediator of lethal systemic inflammation. Acute liver failure (ALF) has been shown to trigger systemic inflammation in clinical and animal studies. To evaluate the possibility of HMGB1 cytoplasmic translocation in ALF, we determined whether HMGB1 is released in hepatocytes and end organ in patients with liver failure/injury. METHODS: HepG2 cell were stimulated with LPS or TNF-α, the increase of HMGB1 extracellularly in the culture medium and intracellularly in various cellular fractions were determined by western blot or immunocytochemistry. To observe sub-cellular location of HMGB1 in hepatocytes, liver specimens were obtained from 6 patients with ALF caused by HBV infection, 10 patients with chronic viral hepatitis B, 6 healthy controls, as well as animals model of ALF by intraperitoneal administration of D-GalN (600 mg/kg) and LPS (0.5 mg/kg). RESULTS: In HepG2 cell culture, LPS or TNF actively induced HMGB1 cytoplasmic translocation and release in a time- and dose-dependent fashion. In animal model of ALF, cytoplasmic HMGB1 translocation was observed in hepatocyts as early as 3 hours post onset of ALF. In patients with ALF caused by HBV infection, cytoplasmic HMGB1 translocation was similarly observed in some hepatocytes of the liver specimen. CONCLUSIONS: Cytoplasmic HMGB1 translocation may occur during ALF, which may potentially contribute to the pathogenesis of liver inflammatory diseases.


Assuntos
Citoplasma/metabolismo , Proteína HMGB1/metabolismo , Hepatócitos/metabolismo , Falência Hepática Aguda/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite B/complicações , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/efeitos dos fármacos
10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 33(12): 1089-94, 2008 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-19141973

RESUMO

OBJECTIVE: To explore the effect of suppressive oligodeoxynucleotides (Sup ODN) on the Th1 differentiation of CD4(+)T splenetic lymphocytes in mice. METHODS: The splenetic lymphocytes of BALB/c mice were separated, and then CD4(+) cells were purified with immune magnetic CD4(+) microbeads (positive selection). The purification was examined by fluorescence-activated cell sorter. CD4(+) cells, anti-CD3epsilon, anti-CD28, IL-12 and Sup ODN or control oligodeoxynucleotides (Con ODN) were co-incubated for 72 h. IFN-gamma and IL-4 in the supernatant were detected using enzyme-linked immunosorbent assay. The expression of T-bet mRNA in CD4(+) cells was tested by reverse transcription polymerase chain reaction. RESULTS: Sup ODN could significantly inhibit the release of INF-gamma and increase IL-4 production respectively (P<0.01). T-bet mRNA of CD4(+) lymphocytes was remarkably inhibited by Sup ODN as well (P<0.01). CONCLUSION: In the presence of pro-Th1-cytokines, Sup ODN may affect the differentiation of CD4(+) T lymphocytes in vitro. Sup ODN can promote CD4(+) T cells to differentiate into Th2, and suppress them into Th1.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Subpopulações de Linfócitos T , Células Th1/imunologia , Animais , Relação CD4-CD8 , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Interferon gama/antagonistas & inibidores , Interferon gama/fisiologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/citologia
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