AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepa...AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.展开更多
Objective： To investigate the effects of soluble factors secreted by acute myeloid leukemia （AML） cells on the phenotypical and functional properties of DCs derived from normal mononuclear cells. Methods： Mononucl...Objective： To investigate the effects of soluble factors secreted by acute myeloid leukemia （AML） cells on the phenotypical and functional properties of DCs derived from normal mononuclear cells. Methods： Mononuclear cells were cultured with interleukin-4 （IL-4） and granulocyte-macrophage colony-stimulating factor （GM-CSF）, in the presence or absence of 24 h culture supematants from fresh pdmary AML cells, to generate immature DCs. The maturation of DCs was induced by cytokines IL-lbeta, IL-6, tumor necrosis factor-alpha （TNF-alpha）, and prostaglandin-2 （PGE-2）. The phenotypic alterations of DCs and DCs-primed CD4＋ T cells were evaluated using flow cytometry. Precursor frequency （PF） was calculated to monitor the allostimulatory effects of DCs on CD4^＋ and CD8^＋ T cells. Results：AML cell supernatant-treated DCs showed significantly lower expression of co-stimulatory molecules CDS0 and CD86, and reduced response to cytokines IL-1beta, IL-6, TNF-alpha, and PGE-2. The allostimulatory effects of AML cell supematant-treated DCs on CD4^＋ and CD8^＋ T cells were significantly lower than those of normal mature DCs [PF： （1.8 ±0.5）% vs. （5.2 ± 1.6）% for CD4^＋ T cells, （2.1 ±0.6）% vs. （6.5 ± 2.0）% for CD8^＋ T cells, P 〈 0.01]. These AML supernatantoinduced DCs could also induce allogeneic CD4^＋ T cells to differentiate into CD4^＋CD25high T cells, which had immunophenotyping characteristics of regulatory T cells, i.e. they expressed Foxp3 but not active maker CD69. Conclusion： This study demonstrates that soluble factors secreted by AML cells can inhibit development and functions of DCs. In addition, AML supernatant-induced DCs can induce the generation of CD4^＋CD25^high T cells from CD4^＋ T cells, which may be a mechanism of increased prevalence of CD4^＋CD25^high regulatory T cells and immune dysfunction in AML patients.展开更多
OBJECTIVE To study the mechanism of IFN on CML.METHODS Samples of 15 CML patients and 10 healthy controlswere studied. The flow cytometry was performed to identifycirculating pDCs. The concentration of IFN-α in serum...OBJECTIVE To study the mechanism of IFN on CML.METHODS Samples of 15 CML patients and 10 healthy controlswere studied. The flow cytometry was performed to identifycirculating pDCs. The concentration of IFN-α in serum and that inthe supernatant of peripheral blood mononuclear cells (PBMCs)cultured after stimulation with CpG ODN2216 were examinedboth in CML patients and in the healthy controlsRESULTS There was significant reduction in the numberof circulating pDCs, serum concentration of IFN-α and thecapacity of IFN-α producing PBMCs in CML patients comparedwith those in healthy control individuals (P < 0.001). After theactive treatment with IFN-α and hydroxyurea, the quantity andfunction of pDCs were increased in stabilized patients, especiallythe function of pDCs in 2 patients achieving major cytogeneticresponse (MCR). The proportion and function of pDCs and theserum levels of IFN were inversely correlated with both WBC andage of the patients with CML, and positively correlated with thestate of the illness.CONCLUSION CML patients had a reduced number anddysfunction of circulating pDCs. The active treatment with IFN inCML patients may be related to the restoration of pDCs.展开更多
Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)in...Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)infection.Since then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect.Dendritic cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging.Reports have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection.Given the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.展开更多
AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma(HCC),in relation to other hepatic diseases.METHODS Eighty-eight patients were included in the current study and represe...AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma(HCC),in relation to other hepatic diseases.METHODS Eighty-eight patients were included in the current study and represented patients with HCC(20),liver cirrhosis(28) and chronic hepatitis(CH;25),and normal controls(NC;15).Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells(m DCs;CD1 c and CD40),mature inactive myeloid cells(CD1 c and HLA),active plasmacytoid cells(p DCs;CD303 and CD40),mature inactive p DCs(CD30 and HLA),active natural killer(NK) cells(CD56 and CD161),active NK cells(CD56 and CD314) and inactive NK cells(CD56 and CD158) was done by flow cytometry.Serum levels of interleukin(IL)-2,IL-10,IL-12,IL-1β,interferon(IFN)-α,IFN-γ and tumor necrosis factor(TNF)-αR2 were assessed by ELISA.RESULTS Active m DCs(CD1 C+/CD40+) and inactive m DCs(CD1 c+/HLA+) were significantly decreased in HCC patients in relation to NC(P < 0.001).CD40+ expression on active p DCs was decreased in HCC patients(P < 0.001),and its level was not significantly changed among other groups.Inactive p DCs(CD303+/HLA+),inactive NKs(CD56+/CD158+) and active NKs(CD56+/CD161+) were not statistically changed among the four groups studied;however,the latter was increased in CH(P < 0.05).NKG2 D was statistically decreased in HCC,CH and cirrhosis(P < 0.001),and it was not expressed in 63%(12/20) of HCC patients.There was significant decrease of IL-2,IFN-α and IFN-γ(P < 0.001),and a significant increase in IL-10,IL-1β,and TNF-αR2(P <0.01,P < 0.001 and P < 0.001;respectively) in HCC patients.There was inverted correlation between IL-12 and IL-1β in HCC(r =-0.565,P < 0.01),with a strong correlation between p DCs(CD303+/CD40+) and NKs(CD56+/CD161+;r = 0.512,P < 0.05) as well as inactive m DCs(CD1 c+/HLA+) and inactive NK cells(CD56+/CD158+;r = 0.945,P < 0.001).CONCLUSION NKG2 D,CD40,IL-2 and IL-10 are important modulators in the development and progression of HCC.展开更多
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor imm...Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.展开更多
OBJECTIVE: To establish a serum-free culture system of dendritic cells (DCs) from chronic myeloid leukemia (CML) cells so that DCs vaccine may be applied to the adoptive immunotherapy of CML in the near future. METHOD...OBJECTIVE: To establish a serum-free culture system of dendritic cells (DCs) from chronic myeloid leukemia (CML) cells so that DCs vaccine may be applied to the adoptive immunotherapy of CML in the near future. METHODS: Fetal calf serum, serum-free medium and autologous serum were used for culture of DCs. The usage of cytokines was classified into two groups: group A (stem cell factor, granulocyte/macrophage colony-stimulating-factor, tumor necrosis factor-alpha and interleukin-4) and group B (granulocyte/macrophage colony-stimulating-factor, tumor necrosis factor-alpha and interleukin-4). The phenotypes of DCs were analyzed by using indirect immunofluorescence and flow cytometry. Mixed leukocyte responses were performed by methyl thiazolyl tetrazolium (MTT) assay. Chromosome analysis of DCs can be achieved by displaying G banding. T cells from CML patients were stimulated with autologous DCs and T-cell cytotoxicity was measured by (MTT) assay. RESULTS: CD34(+) cells or mononuclear cells were obtained from peripheral blood or bone marrow samples of eight patients of chronic-phase CML. Group A of serum-free medium was better than group B in expansion of total cell numbers and the rate of DCs. These results of serum-free medium were not significantly different from those of fetal calf serum medium, but the results of autologous serum medium were inferior to two groups above. The expression of major histocompatibility complex class II antigen on the surface of DCs was notable (> 50%), but the expression of CD83 and the costimulatory molecules CD86 was not noticeable (10% - 50%). Although CD1a(+)/CD14(-) DCs were potent stimulators of allogeneic lymphocytes, expansion of T cells from normal volunteers were not significant (average 27.2 fold at DCs: T cells ratio of 1:10). At day 12, CD1a(+) cells from three patients were studied by displaying G banding and Ph(+) cells in these populations were 100%, 98% and 60%, respectively. At an effector: target ratio of 40:1, 32% to 45% cytotoxicity was noted with DC-stimulated T cells against autologous leukemia cells. CONCLUSIONS: A stable serum-free culture system of CML-DCs was established. The expression of CD83 and CD86 on the surface of CML-DCs and DCs' potent stimulation of allogeneic lymphocytes were not notable. DCs in CML patients can be derived from the malignant clone and these malignant DCs could induce anti-leukemic reactivity in autologous T lymphocytes without the necessity for additional exogenous antigens.展开更多
Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The ...Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells （mDCs） and the efficacy of methylprednisolone （MP） treatment for hepatitis B virus （H BV）-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at lO-day intervals; 26 patients received conservative medical （CM） management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.展开更多
In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel doubl...In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA （dsRNA） sensor in myeloid dendritic cells （mDCs）. The knockdown of DHX33 using small heteroduplex RNA （shRNA） blocked the ability of mDCs to produce type I interferon （IFN） in response to poly hC and reovirus. The HELICc domain of DHX33 was shown to bind poly hC. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 （also referred to MAVS and VISA）. The inhibition of DHX33 expression by RNA interference blocked the poly hC-induced activation of MAP kinases, NF-KB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I-C and RNA viruses in mDCs.展开更多
Introduction:Mature plasmacytoid dendritic cells(pDCs)proliferation associated with myeloid neoplasms(MPDMN)are recognized as a neoplasm related to fully differentiated pDCs.Although it has been reported for many year...Introduction:Mature plasmacytoid dendritic cells(pDCs)proliferation associated with myeloid neoplasms(MPDMN)are recognized as a neoplasm related to fully differentiated pDCs.Although it has been reported for many years,the genomic landscape of MPDMN is poorly understood.Methods:We reported two patients who developed acute myeloid leukemia(French-American-British M5 subtype)coexisted with immunophenotypically mature pDCs proliferation,which fit the diagnosis of MPDMN.We sorted pDCs from myeloid blasts by flow cytometry and performed whole-exome sequencing and RNA sequencing of the two cell populations,respectively.Results:The immunophenotypes of pDCs in both patients were positive for CD123bri,HLA-DR,CD4,CD303,CD304,and negative for CD56,CD34,CD117,and TdT.The variant allele frequency of gene mutations in myeloid blasts and pDCs were similar.The expression data showed myeloid blasts clustered tightly with hematopoietic stem cells,and pDCs from patients clustered tightly with granulocyte-monocyte progenitors/common myeloid progenitor,rather than with pDCs from the GEO platform.Conclusion:Our study suggested that pDCs derived from the leukemic clone,evidenced by a shared mutation profile and similar transcriptional signatures between pDCs and concurrent myeloid blasts.展开更多
Background Smoking causes frequent asthma attacks, leading to a rapid decline in lung function in patients with asthma, and it can also reduce the therapeutic effect of glucocorticoids in patients with asthma. Therefo...Background Smoking causes frequent asthma attacks, leading to a rapid decline in lung function in patients with asthma, and it can also reduce the therapeutic effect of glucocorticoids in patients with asthma. Therefore, the present study aimed to investigate the effect of cigarette smoke on the expression of myeloid differentiation factor 88 （MyD88） in marrow dendritic cells （DCs） in asthmatic rats, and to explore the molecular mechanism of cigarette smoke exposure on asthma by DCs. Methods Forty Wistar rats were randomly divided into the following groups： control, smoke exposure, asthma, and asthma combined with smoke exposure. The animal model was established, and then rat bone marrow-derived DCs were collected. Additionally, rat spleen lymphocytes and bone marrow-derived DCs were cultured together for mixed lymphocyte responses. Interferon （IFN）-gamma and interleukin （IL）-4, IL-10, and IL-12 expressions were determined by enzyme-linked immunosorbent assay （ELISA）. MyD88 expression was determined by Western blotting. The proliferation of lymphocytes was examined with methyl thiazolyl tetrazolium （MTT） colorimetric assay. Results MyD88 expression was decreased in the asthma combined with smoke exposure group compared to the asthma group （P 〈0.01）, and IL-10 and IL-12 expressions were decreased in the asthma combined with smoke exposure group compared to control group （P 〈0.01）. In addition, DCs stimulating activity on allogeneic lymphocytes were significantly decreased in the smoke exposure combined with asthma group compared to the control and asthma groups （P 〈0.01）. After allogeneic mixed lymphocyte responses, IL-4 expression was increased and IFN-gamma was decreased in the asthma group and the asthma combined with smoke exposure group compared to control group （P 〈0.01）. IL-4 expression was increased and IFN-gamma was decreased in the asthma combined with smoke exposure group compared to the asthma group （P 〈0.01）. The study also showed that MyD88 expression was positively correlated with IL-12 and IFN-gamma expressions and the activity of lymphocytes （P 〈0.01）, and negatively correlated with IL-4 expression （P 〈0.01）. Conclusions Smoking aggravates asthma by weankening immunological mechanism. MyD88-dependent pathways may play a role in the immunological balance and activation of lymphocytes.展开更多
In general,acute myeloid leukemia(AML)is an aggressive and heterogeneous disease that is characterized by rapid cellular proliferation and high mortality.One of the mutations related to AML is the Flt3-ITD mutation,wh...In general,acute myeloid leukemia(AML)is an aggressive and heterogeneous disease that is characterized by rapid cellular proliferation and high mortality.One of the mutations related to AML is the Flt3-ITD mutation,which is found in approximately 25%of patients.In this mini-review,we investigate the function of dendritic cells and T cells based on Flt3-ITD mutation and immune evasion as a result of this abnormality.Finally,we discuss some AML therapeutic strategies,including targeting Flt3 on DCs and TIM-3 on T cells as immune receptors to treat this hematopoietic malignancy.展开更多
文摘AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.
基金grants from the National Outstanding Young Investigator Program (30225038)Anhui Provincial Natural Science Foundation (070413094)+1 种基金Scientific Research Fund of Anhui Provincial Education Department (2006KJ072C)Science and Technological Fund of Anhui Province for Outstanding Youth.
文摘Objective： To investigate the effects of soluble factors secreted by acute myeloid leukemia （AML） cells on the phenotypical and functional properties of DCs derived from normal mononuclear cells. Methods： Mononuclear cells were cultured with interleukin-4 （IL-4） and granulocyte-macrophage colony-stimulating factor （GM-CSF）, in the presence or absence of 24 h culture supematants from fresh pdmary AML cells, to generate immature DCs. The maturation of DCs was induced by cytokines IL-lbeta, IL-6, tumor necrosis factor-alpha （TNF-alpha）, and prostaglandin-2 （PGE-2）. The phenotypic alterations of DCs and DCs-primed CD4＋ T cells were evaluated using flow cytometry. Precursor frequency （PF） was calculated to monitor the allostimulatory effects of DCs on CD4^＋ and CD8^＋ T cells. Results：AML cell supernatant-treated DCs showed significantly lower expression of co-stimulatory molecules CDS0 and CD86, and reduced response to cytokines IL-1beta, IL-6, TNF-alpha, and PGE-2. The allostimulatory effects of AML cell supematant-treated DCs on CD4^＋ and CD8^＋ T cells were significantly lower than those of normal mature DCs [PF： （1.8 ±0.5）% vs. （5.2 ± 1.6）% for CD4^＋ T cells, （2.1 ±0.6）% vs. （6.5 ± 2.0）% for CD8^＋ T cells, P 〈 0.01]. These AML supernatantoinduced DCs could also induce allogeneic CD4^＋ T cells to differentiate into CD4^＋CD25high T cells, which had immunophenotyping characteristics of regulatory T cells, i.e. they expressed Foxp3 but not active maker CD69. Conclusion： This study demonstrates that soluble factors secreted by AML cells can inhibit development and functions of DCs. In addition, AML supernatant-induced DCs can induce the generation of CD4^＋CD25^high T cells from CD4^＋ T cells, which may be a mechanism of increased prevalence of CD4^＋CD25^high regulatory T cells and immune dysfunction in AML patients.
基金supported by a grant from the Science and Technology Planning Project of Gansu Province,China(No.2005LZ0627).
文摘OBJECTIVE To study the mechanism of IFN on CML.METHODS Samples of 15 CML patients and 10 healthy controlswere studied. The flow cytometry was performed to identifycirculating pDCs. The concentration of IFN-α in serum and that inthe supernatant of peripheral blood mononuclear cells (PBMCs)cultured after stimulation with CpG ODN2216 were examinedboth in CML patients and in the healthy controlsRESULTS There was significant reduction in the numberof circulating pDCs, serum concentration of IFN-α and thecapacity of IFN-α producing PBMCs in CML patients comparedwith those in healthy control individuals (P < 0.001). After theactive treatment with IFN-α and hydroxyurea, the quantity andfunction of pDCs were increased in stabilized patients, especiallythe function of pDCs in 2 patients achieving major cytogeneticresponse (MCR). The proportion and function of pDCs and theserum levels of IFN were inversely correlated with both WBC andage of the patients with CML, and positively correlated with thestate of the illness.CONCLUSION CML patients had a reduced number anddysfunction of circulating pDCs. The active treatment with IFN inCML patients may be related to the restoration of pDCs.
基金Supported by Robert W Storr Bequest to the Sydney Medical Foundation Work program and a National Health and Medical Research Council of Australia(NHMRC)Program Grant,APP1053206(to George J and Ahlenstiel G)research grants from the NHMRC(partly),APP1006759 and ARC Linkage Grant,LP0990067the Hunt Family Senior Research Fellowship(to Booth D)
文摘Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)infection.Since then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect.Dendritic cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging.Reports have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection.Given the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.
文摘AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma(HCC),in relation to other hepatic diseases.METHODS Eighty-eight patients were included in the current study and represented patients with HCC(20),liver cirrhosis(28) and chronic hepatitis(CH;25),and normal controls(NC;15).Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells(m DCs;CD1 c and CD40),mature inactive myeloid cells(CD1 c and HLA),active plasmacytoid cells(p DCs;CD303 and CD40),mature inactive p DCs(CD30 and HLA),active natural killer(NK) cells(CD56 and CD161),active NK cells(CD56 and CD314) and inactive NK cells(CD56 and CD158) was done by flow cytometry.Serum levels of interleukin(IL)-2,IL-10,IL-12,IL-1β,interferon(IFN)-α,IFN-γ and tumor necrosis factor(TNF)-αR2 were assessed by ELISA.RESULTS Active m DCs(CD1 C+/CD40+) and inactive m DCs(CD1 c+/HLA+) were significantly decreased in HCC patients in relation to NC(P < 0.001).CD40+ expression on active p DCs was decreased in HCC patients(P < 0.001),and its level was not significantly changed among other groups.Inactive p DCs(CD303+/HLA+),inactive NKs(CD56+/CD158+) and active NKs(CD56+/CD161+) were not statistically changed among the four groups studied;however,the latter was increased in CH(P < 0.05).NKG2 D was statistically decreased in HCC,CH and cirrhosis(P < 0.001),and it was not expressed in 63%(12/20) of HCC patients.There was significant decrease of IL-2,IFN-α and IFN-γ(P < 0.001),and a significant increase in IL-10,IL-1β,and TNF-αR2(P <0.01,P < 0.001 and P < 0.001;respectively) in HCC patients.There was inverted correlation between IL-12 and IL-1β in HCC(r =-0.565,P < 0.01),with a strong correlation between p DCs(CD303+/CD40+) and NKs(CD56+/CD161+;r = 0.512,P < 0.05) as well as inactive m DCs(CD1 c+/HLA+) and inactive NK cells(CD56+/CD158+;r = 0.945,P < 0.001).CONCLUSION NKG2 D,CD40,IL-2 and IL-10 are important modulators in the development and progression of HCC.
基金Supported by(in part)Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B(No.17fk0310116h0001) from the Japan Agency for Medical Research and Development(AMED)Extramural Collaborative Research Grant of Cancer Research Institute,Kanazawa University
文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
基金ThisresearchwassupportedbyagrantfromtheShannxiProvincialScienceFoundationofPublicHealthBureau (No .0 0 12 2 )
文摘OBJECTIVE: To establish a serum-free culture system of dendritic cells (DCs) from chronic myeloid leukemia (CML) cells so that DCs vaccine may be applied to the adoptive immunotherapy of CML in the near future. METHODS: Fetal calf serum, serum-free medium and autologous serum were used for culture of DCs. The usage of cytokines was classified into two groups: group A (stem cell factor, granulocyte/macrophage colony-stimulating-factor, tumor necrosis factor-alpha and interleukin-4) and group B (granulocyte/macrophage colony-stimulating-factor, tumor necrosis factor-alpha and interleukin-4). The phenotypes of DCs were analyzed by using indirect immunofluorescence and flow cytometry. Mixed leukocyte responses were performed by methyl thiazolyl tetrazolium (MTT) assay. Chromosome analysis of DCs can be achieved by displaying G banding. T cells from CML patients were stimulated with autologous DCs and T-cell cytotoxicity was measured by (MTT) assay. RESULTS: CD34(+) cells or mononuclear cells were obtained from peripheral blood or bone marrow samples of eight patients of chronic-phase CML. Group A of serum-free medium was better than group B in expansion of total cell numbers and the rate of DCs. These results of serum-free medium were not significantly different from those of fetal calf serum medium, but the results of autologous serum medium were inferior to two groups above. The expression of major histocompatibility complex class II antigen on the surface of DCs was notable (> 50%), but the expression of CD83 and the costimulatory molecules CD86 was not noticeable (10% - 50%). Although CD1a(+)/CD14(-) DCs were potent stimulators of allogeneic lymphocytes, expansion of T cells from normal volunteers were not significant (average 27.2 fold at DCs: T cells ratio of 1:10). At day 12, CD1a(+) cells from three patients were studied by displaying G banding and Ph(+) cells in these populations were 100%, 98% and 60%, respectively. At an effector: target ratio of 40:1, 32% to 45% cytotoxicity was noted with DC-stimulated T cells against autologous leukemia cells. CONCLUSIONS: A stable serum-free culture system of CML-DCs was established. The expression of CD83 and CD86 on the surface of CML-DCs and DCs' potent stimulation of allogeneic lymphocytes were not notable. DCs in CML patients can be derived from the malignant clone and these malignant DCs could induce anti-leukemic reactivity in autologous T lymphocytes without the necessity for additional exogenous antigens.
基金ACKNOWLEDGEMENTS This study is supported by the National Natural Science Foundation of China （Nos. 30801039 and 81072424） and the major projects of viral hepatitis from Beijing Municipal Science and Technology Commission （No. H020920020890）. We thank the volunteers who generously participated in this study.
文摘Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells （mDCs） and the efficacy of methylprednisolone （MP） treatment for hepatitis B virus （H BV）-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at lO-day intervals; 26 patients received conservative medical （CM） management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.
文摘In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA （dsRNA） sensor in myeloid dendritic cells （mDCs）. The knockdown of DHX33 using small heteroduplex RNA （shRNA） blocked the ability of mDCs to produce type I interferon （IFN） in response to poly hC and reovirus. The HELICc domain of DHX33 was shown to bind poly hC. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 （also referred to MAVS and VISA）. The inhibition of DHX33 expression by RNA interference blocked the poly hC-induced activation of MAP kinases, NF-KB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I-C and RNA viruses in mDCs.
基金was supported in part by State Key Program of National Natural Science of China(81830005)J.W.,National Natural Science Foundation of China(81770181)+3 种基金J.W.,National Key Research and Development Program of China(2019YFC0840605)Y.M.,Tianjin Natural Science Foundation(18JCZDJC45000)H.W.,CAMS Innovation Fund for Medical Sciences(2020-I2M-C&T-B-084)H.W.Funders had no role in the study design,analyses,or decision to publish.
文摘Introduction:Mature plasmacytoid dendritic cells(pDCs)proliferation associated with myeloid neoplasms(MPDMN)are recognized as a neoplasm related to fully differentiated pDCs.Although it has been reported for many years,the genomic landscape of MPDMN is poorly understood.Methods:We reported two patients who developed acute myeloid leukemia(French-American-British M5 subtype)coexisted with immunophenotypically mature pDCs proliferation,which fit the diagnosis of MPDMN.We sorted pDCs from myeloid blasts by flow cytometry and performed whole-exome sequencing and RNA sequencing of the two cell populations,respectively.Results:The immunophenotypes of pDCs in both patients were positive for CD123bri,HLA-DR,CD4,CD303,CD304,and negative for CD56,CD34,CD117,and TdT.The variant allele frequency of gene mutations in myeloid blasts and pDCs were similar.The expression data showed myeloid blasts clustered tightly with hematopoietic stem cells,and pDCs from patients clustered tightly with granulocyte-monocyte progenitors/common myeloid progenitor,rather than with pDCs from the GEO platform.Conclusion:Our study suggested that pDCs derived from the leukemic clone,evidenced by a shared mutation profile and similar transcriptional signatures between pDCs and concurrent myeloid blasts.
文摘Background Smoking causes frequent asthma attacks, leading to a rapid decline in lung function in patients with asthma, and it can also reduce the therapeutic effect of glucocorticoids in patients with asthma. Therefore, the present study aimed to investigate the effect of cigarette smoke on the expression of myeloid differentiation factor 88 （MyD88） in marrow dendritic cells （DCs） in asthmatic rats, and to explore the molecular mechanism of cigarette smoke exposure on asthma by DCs. Methods Forty Wistar rats were randomly divided into the following groups： control, smoke exposure, asthma, and asthma combined with smoke exposure. The animal model was established, and then rat bone marrow-derived DCs were collected. Additionally, rat spleen lymphocytes and bone marrow-derived DCs were cultured together for mixed lymphocyte responses. Interferon （IFN）-gamma and interleukin （IL）-4, IL-10, and IL-12 expressions were determined by enzyme-linked immunosorbent assay （ELISA）. MyD88 expression was determined by Western blotting. The proliferation of lymphocytes was examined with methyl thiazolyl tetrazolium （MTT） colorimetric assay. Results MyD88 expression was decreased in the asthma combined with smoke exposure group compared to the asthma group （P 〈0.01）, and IL-10 and IL-12 expressions were decreased in the asthma combined with smoke exposure group compared to control group （P 〈0.01）. In addition, DCs stimulating activity on allogeneic lymphocytes were significantly decreased in the smoke exposure combined with asthma group compared to the control and asthma groups （P 〈0.01）. After allogeneic mixed lymphocyte responses, IL-4 expression was increased and IFN-gamma was decreased in the asthma group and the asthma combined with smoke exposure group compared to control group （P 〈0.01）. IL-4 expression was increased and IFN-gamma was decreased in the asthma combined with smoke exposure group compared to the asthma group （P 〈0.01）. The study also showed that MyD88 expression was positively correlated with IL-12 and IFN-gamma expressions and the activity of lymphocytes （P 〈0.01）, and negatively correlated with IL-4 expression （P 〈0.01）. Conclusions Smoking aggravates asthma by weankening immunological mechanism. MyD88-dependent pathways may play a role in the immunological balance and activation of lymphocytes.
文摘In general,acute myeloid leukemia(AML)is an aggressive and heterogeneous disease that is characterized by rapid cellular proliferation and high mortality.One of the mutations related to AML is the Flt3-ITD mutation,which is found in approximately 25%of patients.In this mini-review,we investigate the function of dendritic cells and T cells based on Flt3-ITD mutation and immune evasion as a result of this abnormality.Finally,we discuss some AML therapeutic strategies,including targeting Flt3 on DCs and TIM-3 on T cells as immune receptors to treat this hematopoietic malignancy.
