枯否细胞的负向免疫调节作用

目前认为肝脏是淋巴器官,它倾向于产生免疫耐受而非免疫应答。枯否细胞(KC)是肝内固有的巨噬细胞,其在发挥免疫防御的过程中可释放多种化学介质介导肝损伤并参与肝纤维化的病理改变。近来研究发现活化的KC与肝脏免疫耐受的形成和维持有关,KC能够分泌免疫抑制性细胞因子,抑制T细胞增殖并诱导T细胞凋亡,从而发挥负向免疫调节功能。对KC负向免疫调控的研究将大大拓展对致耐受性APC尤其是巨噬细胞的认识与理解,为深入研究肝脏内环境稳定和免疫耐受形成的机制开拓新的思路。     

调节性T细胞及其CD45亚群在肝移植免疫耐受中的相关研究

调节性T细胞(Tr)作为一种具有免疫抑制功能的细胞在器官移植免疫耐受中发挥了重要作用.它通过细胞接触抑制排斥反应发生、诱导移植免疫耐受,并且这种免疫抑制具有免疫过继作用.其中CD45亚群被认为是Tr中抑制功能较强的一群细胞,在移植免疫耐受中发挥着重要作用.而肝脏作为一种免疫特惠器官,与其他器官移植相比更易产生免疫耐受....     

树突状细胞诱导T细胞免疫耐受的机理

DC是一类专职的抗原呈递细胞 ,不仅具有强大的免疫应答诱导能力 ,而且能够通过多种机制诱导T细胞产生抗原特异性免疫耐受 ,这些机制包括诱导T细胞无能、专职地释放免疫抑制性细胞因子、介导T细胞的克隆清除、诱导和募集调节性T细胞和诱导免疫偏离。DC诱导免疫耐受机制研究的深入必将为DC的临床应用提供更坚实的基础。     

免疫耐受的形成、维持及诱导

日益突出的自身免疫病及移植排斥问题为进一步深入认识免疫耐受形成及维持的机制提出了迫切要求。本文综述了免疫应答的启动、免疫耐受形成、维持机制以及免疫耐受诱导等几方面最新的研究进展。     

087 树突状细胞诱导T细胞免疫耐受的机理

摘要DC是一类专职的抗原呈递细胞,不仅具有强大的免疫应答诱导能力,而且能够通过多种机制诱导T细胞产生抗原特异性免疫耐受,这些机制包括诱导T细胞无能、专职地释放免疫抑制性细胞因子、介导T细胞的克隆清除、诱导和募集调节性T细胞和诱导免疫偏离.DC诱导免疫耐受机制研究的深入必将为DC的临床应用提供更坚实的基础.     

免疫耐受的形成、维持及诱导

日益突出的自身免疫病及移植排斥问题为进一步深入认识免疫耐受形成及维持的机制提出了迫切要求。本文综述了免疫应答的启动、免疫耐受形成、维持机制以及免疫耐受诱导等几方面最新的研究进展。     

树突状细胞诱导T细胞免疫耐受的机理

DC是一类专职的抗原呈递细胞，不仅具有强大的免疫应答诱导能力，而且能够通过多种机制诱导T细胞产生抗原特异性免疫耐受，这些机制包括诱导T细胞无能、专职地释放免疫抑制性细胞因子、介导T细胞的克隆清除、诱导和募集调节性T细胞和诱导免疫偏离。DC诱导免疫耐受机制研究的深入必将为DC的临床应用提供更坚实的基础。     

吲哚胺2,3双加氧酶(IDO)的免疫调节作用

吲哚胺 2 ,3双加氧酶 (indoleamine 2 ,3 dioxygenase ,IDO )是肝脏以外唯一可催化色氨酸沿犬尿酸途径分解代谢的限速酶 ,在哺乳动物的组织与细胞 ,尤其是淋巴组织和胎盘中广泛表达。它通过降解局部组织中的色氨酸 ,在诱发宿主免疫防御、抑制T细胞免疫和抗肿瘤免疫、诱导母胎免疫耐受和移植物免疫耐受中均发挥重要的代谢性免疫调节作用。     

抗原诱导免疫耐受的历史回顾和研究现状

供者特异性抗原已成为成年动物诱导免疫耐受的主要方法之一，本文就输血，脾细胞和骨髓细胞在诱导免疫耐受中的作用，机理及肝脏和胸腺作用为特殊免疫器官在耐受形成和维持中的地位进行综述。     

肝纤维化肝窦内皮细胞免疫功能改变的研究进展

正常肝脏是免疫耐受大于免疫原性的器官,肝窦内皮细胞(HSEC)在参与正常肝脏免疫耐受方面的研究是热点。在肝脏疾病中,很少有关HSEC免疫方面的研究。肝纤维化过程中,HSEC结构和功能的改变,可能造成其免疫功能的转变(免疫耐受转化为免疫应答),但HSEC免疫功能的转变,也可能影响肝纤维化的进程,研究纤维化肝脏肝窦内皮细胞(FH-SEC)免疫功能,对应用免疫手段治疗肝纤维化有重要意义。     

Gut immune response in the presence of hepatitis C virus infection

Hepatitis C virus(HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extrahepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28Bgenotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.     

Pathogenesis of hepatitis B virus infection

The adaptive immune response is thought to be responsible for viral clearance and disease pathogenesis during hepatitis B virus infection. It is generally acknowledged that the humoral antibody response contributes to the clearance of circulating virus particles and the prevention of viral spread within the host while the cellular immune response eliminates infected cells. The T cell response to the hepatitis B virus (HBV) is vigorous, polyclonal and multispecific in acutely infected patients who successfully clear the virus and relatively weak and narrowly focussed in chronically infected patients, suggesting that clearance of HBV is T cell dependent. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been proven by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg specific CTL into HBV transgenic mice. Remarkably, the CTLs also purge HBV replicative intermediates from the liver by secreting type 1 inflammatory cytokines thereby limiting virus spread to uninfected cells and reducing the degree of immunopathology required to terminate the infection. Persistent HBV infection is characterized by a weak adaptive immune response, thought to be due to inefficient CD4+ T cell priming early in the infection and subsequent development of a quantitatively and qualitatively ineffective CD8+ T cell response. Other factors that could contribute to viral persistence are immunological tolerance, mutational epitope inactivation, T cell receptor antagonism, incomplete down-regulation of viral replication and infection of immunologically privileged tissues. However, these pathways become apparent only in the setting of an ineffective immune response, which is, therefore, the fundamental underlying cause. Persistent infection is characterized by chronic liver cell injury, regeneration, inflammation, widespread DNA damage and insertional deregulation of cellular growth control genes, which, collectively, lead to cirrhosis of the liver and hepatocellular carcinoma.     

NK cells in immunotolerant organs

Organs such as the liver, uterus and lung possess hallmark immunotolerant features, making these organs important for sustaining self-homeostasis. These organs contain a relatively large amount of negative regulatory immune cells, which are believed to take part in the regulation of immune responses. Because natural killer cells constitute a large proportion of all lymphocytes in these organs, increasing attention has been given to the roles that these cells play in maintaining immunotolerance. Here, we review the distribution, differentiation, phenotypic features and functional features of natural killer cells in these immunotolerant organs, in addition to the influence of local microenvironments on these cells and how these factors contribute to organ-specific diseases.     

Transferrin and ferritin response to bacterial infection: The role of the liver and brain in fish

Iron is essential for growth and survival, but it is also toxic when in excess. Thus, there is a tight regulation of iron that is accomplished by the interaction of several genes including the iron transporter transferrin and iron storage protein ferritin. These genes are also known to be involved in response to infection. The aim of this study was to understand the role of transferrin and ferritin in infection and iron metabolism in fish. Thus, sea bass transferrin and ferritin H cDNAs were isolated from liver, cloned and characterized. Transferrin constitutive expression was found to be highest in the liver, but also with significant expression in the brain, particularly in the highly vascularized region connecting the inferior lobe of the hypothalamus and the saccus vasculosus. Ferritin, on the other hand, was expressed in all tested organs, but also significantly higher in the liver. Fish were subjected to either experimental bacterial infection or iron modulation and transferrin and ferritin mRNA expression levels were analyzed, along with several iron regulatory parameters. Transferrin expression was found to decrease in the liver and increase in the brain in response to infection and to increase in the liver in iron deficiency. Ferritin expression was found to inversely reflect transferrin in the liver, increasing in infection and iron overload and decreasing in iron deficiency, whereas in the brain, ferritin expression was also increased in infection. These findings demonstrate the evolutionary conservation of transferrin and ferritin dual functions in vertebrates, being involved in both the immune response and iron metabolism.     

The innate immune response under the control of the LXR pathway

Macrophages play essential roles in infection and resolution of inflammation. This review summarizes recent findings that suggest a relevant role for the nuclear receptor liver X receptor (LXR) in the evolution of immune responses. By exerting both positive and negative regulation of specific macrophage gene expression networks, LXRs display anti-inflammatory activities and promote macrophage survival in bacterial infection settings. Agonists that activate the LXR pathway may be used to enhance innate immunity to highly virulent pathogens that otherwise induce macrophage apoptosis as a means to subvert host immune defense.     

Leishmania infantum antigens modulate memory cell subsets of liver resident T lymphocyte

In the recent years, the liver has been recognized as an important immune organ with major regulatory functions and immune memory, adding to the well-described vital metabolic functions. There are evidences from experimental infections performed with visceral Leishmania species that immune responses to parasite infection can be organ-specific. The liver is the compartment of acute resolving infection, with minimal tissue damage and resistance to reinfection, whereas the spleen is the compartment of parasite persistence. Control of hepatic infection in mice requires a coordinated immune response that involves the development of inflammatory granulomas. It is also described that the liver harbors populations of resident lymphocytes, which may exhibit memory characteristics. Therefore, the present study aims to address the role of the liver as an immune memory organ in the context of Leishmania infantum infection, by characterizing phenotypically resident liver T lymphocytes. The dynamics of memory T cells in L. infantum infected BALB/c mice and the effect of anti-leishmanial treatment in the differentiation of memory cell subsets were analyzed. The potential of recognition, differentiation and selection of memory lymphocytes by three L. infantum recombinant proteins were also explored. L. infantum infection generates effector and central memory T cells, but the cells did not expand when recalled, demonstrating a possible parasite silencing effect. The treatment with a leishmanicidal drug (antimoniate meglumine) increases the levels of memory and effector T cells, eliciting a more robust hepatic immune response. L. infantum parasites with a decreased sensitivity to the leishmanicidal drug favor the expansion of memory CD8⁺ T cell subset, but inhibit the proliferation of CD8⁺ T effector cells, possibly assuring their own survival. The recombinant proteins LirCyp1 and LirSOD are strongly recognized by memory cells of treated mice, indicating that these proteins might be used in a prophylactic or therapeutic vaccine formulation. Thus, L. infantum released antigens induce the development of immune memory subsets in the liver resident T cell population that specifically recognized parasite antigens, including recombinant proteins.     

Neuroendocrine immunomodulation

Close interaction between the immune and nervous systems is well documented. The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved. The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers. Receptors to a number of cytokines have been found in the nervous tissue. Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the role of the "major" stress hormones such as cortisol, DHEA, growth hormone in the regulation of immune response, as well as neuro- and psychotropic properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.     

Immunogenetic analysis of patients with post-schistosomal liver cirrhosis in man

Immune responsiveness of 121 patients with post-schistosomal liver cirrhosis to schistosomal antigens was investigated. Out of 78 patients, only five (6.4%) showed low responsiveness to schistosomal adult worm antigen whereas 73 (93.6%) were high responders. Out of 57 healthy individuals with previous schistosomal infection, low responders were found in 17.5%. The frequency of low responders to schistosomal adult worm antigen was significantly decreased in the patients with post-schistosomal liver cirrhosis (P less than 0.05). Out of 121 patients, a significant increase in frequency of HLA-Bw44-DEn haplotype was observed (corrected P less than 0.02). On the other hand, HLA-Bw52-Dw12 haplotype which was reported to be in strong linkage disequilibrium with an immune suppression gene for schistosomal adult worm antigen was significantly decreased (corrected P less than 0.005). These observations suggested that an HLA-linked immune suppression gene controlled susceptibility or resistance to post-schistosomal liver cirrhosis through regulation of immune responsiveness of the hosts to schistosomal antigen in man.     

Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses

DC are believed to play important roles in the induction and regulation of immune responses in the liver, an organ implicated in peripheral tolerance. Since the liver is located downstream of the gut, it is constantly exposed to bacterial LPS. Our recent observations indicate that prior exposure to endotoxin modulates subsequent liver DC responses to this TLR4 ligand. In this study, we demonstrate that endotoxin modifies the capacity of mouse liver myeloid DC (MDC) activated by CpG (TLR9 ligand) to direct Th1-type responses. IL-12 production by liver MDC was significantly lower than that of spleen MDC following CpG or Imiquimod (R837; TLR7 ligand) activation in vitro. In addition, allogeneic T cells stimulated by CpG-activated liver MDC secreted significantly lower levels of IFN-gamma than T cells stimulated with CpG-activated spleen MDC. A similar effect on liver DC was observed in response to in vivo CpG administration. This effect may be explained by exposure of the DC to endotoxin, because LPS attenuated IL-12 production by CpG-stimulated liver MDC, both in vitro and in vivo. Moreover, attenuation of the response to CpG was not observed in liver MDC from TLR4-mutant (C3H/HeJ) mice, in which TLR4 signaling is impaired. These data suggest that endotoxin-induced 'cross-tolerance' to TLR ligands in liver DC may contribute to down-regulation of hepatic immune responses.