热休克蛋白70的功能及其在寄生虫生长发育中的作用

热休克蛋白（heat shock protein,HSP）也称应激蛋白,具有分子伴侣活性。外源性HSP70能被宿主抗原提呈细胞（antigen presenting cell,APC）识别,引起前炎症反应及获得性免疫应答,而自体HSP70则具有抗炎效应。在最近的研究中还发现HSP70具有佐剂功效,能增强机体对其他抗原肽的免疫应答反应。HSP70在寄生虫的生长发育过程中也起着重要作用。     

热休克蛋白70与肠道病毒感染

热休克蛋白70 (HSP70)是HSP70家族中的重要成员.HSP70的主要功能是作为分子伴侣参与蛋白质的折叠与修饰.在病毒感染时,HSP70参与机体的抗感染免疫,从而保护细胞.因而研究HSP70与肠道病毒的相互作用具有意义.     

HSP110与肿瘤免疫

热休克蛋白(heat shock protein,HSP)是在细胞应激下显著高表达的蛋白质,对于蛋白质转运、折叠和解离起重要作用。其免疫学活性最引人注目,包括:作为分子伴侣来结合抗原多肽,经由抗原递呈细胞递呈给MHC分子进而诱导特异免疫;可作为危险信号启动固有免疫;是良好的免疫佐剂。比之其它HSP,HSP110做为一种效应显著的免疫佐剂,具有更强势的伴侣功能和多肽结合能力。近年较多基础研究提示HSP110增强了相关肿瘤表位多肽、肿瘤相关抗原的特异性肿瘤免疫和抗肿瘤效应。此外,关于肾癌、黑色素瘤的双盲多中心Ⅱ及Ⅲ期临床试验提示HSP抗原肽复合物在肿瘤免疫治疗中安全有效。在此我们综述了HSP110的免疫学功能和肿瘤免疫中的应用。     

热休克蛋白70与肝癌

热休克蛋白70(HSP70)广泛存在于细胞中,在应激刺激后过表达,可以参与蛋白质的合成及受损蛋白的修复。HSP70在肝癌治疗中的作用日益受到重视:利用其特异性和免疫原性,靶向治疗肝癌。并且可以利用其"分子伴侣"的特点,作为肝癌疫苗,诱发机体抗肝癌的免疫反应。HSP70在肝癌治疗中已初显成效,但也存在很多问题,需要更加深入的研究。总之,HSP70在肝癌治疗中有很大的应用前景。     

热休克蛋白与心肌保护

热休克蛋白是一种在正常细胞中普遍表达的蛋白质,可在机体应激的情况下表达增加,通过分子伴侣作用对其他蛋白质的折叠、降解起重要作用。同时,还具有抗氧化、抗细胞凋亡及协同免疫的作用。高温、缺血缺氧预适应均能诱导机体HSP表达增加,产生心脏保护作用。     

热休克蛋白的应用前景

在不利的环境中,机体都有共同的反应,即正常基因的表达抑制和一组特殊基因热休克基因的激活和表达,这一普遍的生物现象称为热休克反应,其产物热休克蛋白是一组非常保守的蛋白分子家族。它们介导其它蛋白质的跨膜转运和正确装配,起着“分子伴侣”的重要作用,与细胞的许多重要生理过程相关,在维持细胞正常功能上起关键作用。由于它具有高度保守性及众多的生物学功能,其研究日益受到广泛重视。     

HSP90抑制剂在急性髓细胞白血病治疗中的最新研究进展

热休克蛋白90(HSP90)是许多癌基因下游蛋白的分子伴侣,参与多重致癌途径,涉及急性髓细胞白血病(AML)的发生和不良预后。HSP90抑制剂是当前AML分子靶向治疗研究药物之一,通过抑制HSP90同时实现对多重致癌信号通路的调控发挥抗白血病作用。     

热休克蛋白与肿瘤免疫

热休克蛋白 (HSPs)作为分子伴侣参与蛋白的合成、折叠、装配、运输和降解。许多肿瘤细胞表面可以高表达HSPs ,它能与癌基因、抑癌基因产物结合。现认为HSPs具有伴移抗原肽的作用 ,肿瘤组织中提取的HSP—肽复合物可以作为肿瘤排斥抗原 ,诱导肿瘤特异性免疫 ,产生特异细胞毒性T细胞 (CTL) ,特异杀伤肿瘤细胞。这种作用在同种间不受MHC 1类分子限制 ,具有很好的临床应用前景。本文主要综述HSP—肽复合物与肿瘤免疫的相关进展。     

HSP90抑制剂在急性髓细胞白血病治疗中的最新研究进展简

 热休克蛋白90(HSP90)是许多癌基因下游蛋白的分子伴侣,参与多重致癌途径,涉及急性髓细胞白血病（AML) 的发生和不良预后。HSP90抑制剂是当前AML分子靶向治疗研究药物之一,通过抑制HSP90同时实现对多重致癌信号通路的调控发挥抗白血病作用。     

热休克蛋白与肿瘤的免疫治疗

热休克蛋白是在细胞内广泛分布、高度保守的蛋白质分子,能与细胞内多种肽分子结合,通过抗原提呈细胞上的受体,将抗原肽经MHCⅠ类途径传递给CD8~ 的细胞毒T细胞,诱导特异性抗肿瘤免疫应答。HSP与肿瘤的关系已成为当前研究的热点之一,热休克蛋白肽复合物作为一种肿瘤疫苗,在肿瘤治疗方面具有广阔的应用前景。     

Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy

Stress or heat shock proteins (HSPs) are the most conserved proteins present in both prokaryotes and eukaryotes. Their expression is induced in response to a wide variety of physiological and environmental insults. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and preventing their aggregation. HSPs have a dual function depending on their intracellular or extracellular location. Intracellular HSPs have a protective function. They allow the cells to survive lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several HSPs have also been demonstrated to directly interact with various components of the tightly regulated programmed cell death machinery, upstream and downstream of the mitochondrial events. On the other hand, extracellular located or membrane-bound HSPs mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. This review will focus on HSP27, HSP70, and HSP90. We will discuss the dual role of these HSPs, protective vs. immunogenic properties, making a special emphasis in their utility as targets in cancer therapy.     

Immunostimulatory properties of the Leishmania infantum heat shock proteins HSP70 and HSP83

Emerging evidence indicates that the heat shock proteins (HSPs), a set of highly evolutionary conserved proteins, are playing essential roles in both normal processes of the immune system and specific immune responses. In a previous work, we demonstrated that the Leishmania infantum HSP70 possesses remarkable immunostimulatory properties. In the present work, we have extended the study to another HSP from this parasite, the HSP83. We show that this protein also has an adjuvant effect to an accompanying protein by stimulation of the humoral response when both proteins are fused and co-administered to BALBjc mice. The analysis of the IgG isotypes, IgG1 and IgG2a, indicated that the immunisations with the Leishmania HSPs, mainly the HSP70, potentiate a Thl-type response. It was found that the amino-terminal domain of the HSP70, the most evolutionary conserved region of the molecule, maintains the ability to stimulate the humoral response, whereas the carboxyl-terminal domain does not have a similar effect. Unexpectedly, we found that the L. infantum HSP70 and HSP83 recombinant proteins stimulated the proliferation of spleen cells from unprimed BALB/c mice. Remarkably, this proliferation was abolished either by thermal denaturing of the proteins or by using specific antibodies. The use of the T-cell inhibitor cyclosporin A in the splenocytes proliferation assays suggested that both T- and non-T-cells are stimulated by the Leishmania HSPs. These findings may be relevant for therapeutic and prophylactic applications.     

Heat shock protein-antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion

Heat shock proteins (HSPs) induce cross-presentation of antigens by dendritic cells (DC) as well as DC maturation. These properties make HSP antigen complexes good candidates to prime CD8 T cell responses against tumor-associated antigens. In this study, we analyzed four different members of the HSP70 family fused to a fragment of ovalbumin (OVA) as a model tumor antigen. E. coli-derived recombinant HSP70-OVA fusion proteins efficiently primed antigen-specific cytotoxic T cells in short-term in vivo immunization assays. Because of concerns that the adjuvant effect of HSPs may be due to endotoxin contamination, we studied this issue in detail. Induction of OVA-specific cytotoxicity was significantly decreased in mice deficient for the LPS receptor, TLR4. After careful removal of endotoxins, immunization with HSP70-OVA failed to prime cytotoxic T cell responses. However, we obtained strong in vivo kill responses when endotoxin-depleted HSP70-OVA was used in combination with the TLR9 ligand CpG oligodeoxynucleotide 1668. Importantly, prophylactic and therapeutic treatment with endotoxin-depleted HSP70-OVA together with CpG significantly delayed the outgrowth of OVA-expressing B16 melanoma cells. However, we were unable to detect significant differences in the magnitudes of immune responses against endotoxin-depleted recombinant OVA vs. endotoxin-depleted HSP70-OVA fusion protein. Thus, immunization with recombinant HSP70-antigen fusion protein does not provide an advantage over recombinant antigen alone when combined with a suitable adjuvant. Altogether, our data suggest that the adjuvant effect of the HSP70 part of the fusion protein is completely lost after endotoxin removal.     

Role for heat shock proteins in the immune response to measles virus infection

Heat shock proteins (HSPs) are recognized for their support of protein metabolism. Interaction with viral proteins also enhances the development of innate and adaptive immune responses against the infecting agent. At the level of the infected cell, HSPs are uniquely expressed on the cell surface, where they represent targets of lymphokine activated killer cells. Necrosis of the infected cell releases complexes of HSP and viral protein, which, in turn, binds antigen-presenting cells (APCs). One effect of binding is to stimulate APC maturation and the release of proinflammatory cytokines, an adjuvant effect that prepares the way for adaptive immune responses. A second effect of binding is to direct the antigenic cargo of the HSP into endogenous MHC presentation pathways for priming of naive cytotoxic T cells (CTL) or activation of antigen-specific CTLs. This alternate pathway of antigen presentation is essential to CTL priming following primary brain infection. Using heat shock to elevate brain levels of HSP in a mouse model of measles virus (MV) persistent infection, we provide evidence supporting a role for HSPs in promoting cell-mediated viral clearance from brain. The findings highlight the probable relevance of HSPs to anti-MV immunity, suggesting novel routes of both therapeutic intervention and preventative measures.     

The Immunomodulatory Effect of Heat Shock Protein 70: Immunization with a DNA Construct Based on the Malarial Antigen Fused with a Fragment of HSP 70 Primes for a Th-1 Type of Response

Finding an appropriate adjuvant for human vaccination is crucial. Heat shock proteins (HSPs) act as adjuvants when coadministered with peptide antigens or given as fusion proteins. However, there is a potential risk of autoimmunity when using the complete molecules, because HSPs are evolutionary conserved. To overcome this, we first evaluated the adjuvant effect against two different antigens of a less-conserved fraction of Plasmodium falciparum HSP70 (Pf70C) and compared it to the whole HSP70 molecule from Trypanosoma cruzi (TcHSP70). We found that Pf70C exhibited similar adjuvant properties as the whole molecule. We later evaluated the adjuvant potential of Pf70C against the malarial antigen EB200 in a chimeric DNA construct. No appreciable levels of EB200-specific antibodies were detected in mice immunized only with the DNA constructs. However, DNA primed the immune system, because subsequent challenge with the corresponding recombinant fusion proteins elicited a strong Th-1 antibody response. In contrast, no priming effect was observed for ex vivo IFN-γ production but stimulation with the HSP-chimeric fusion protein induced a stronger secretion of IFN-γ in vitro than other proteins used. These results indicate that the use of HSPs is promising in the design of new vaccines.     

Chaperones in the parotid gland: localization of heat shock proteins in human adult salivary glands

Heat shock proteins (HSPs) are expressed or increased in response to various biological stresses. Moreover, these 'stress proteins' seem to be expressed by some cells living in physiological conditions. From then on, they could play an important physiological role in normal cell functioning. The best-known physiological role of these HSP proteins is to act as 'molecular chaperones'. In this context, we have investigated the immunohistochemical expression of HSP27, HSP70, HSP90 and HSP110 in 10 human adult salivary glands. To highlight the presence of RNAm encoding HSP70, an in situ hybridization was performed. In our material, HSP27 was strongly expressed in the cytoplasm of striated duct cells and in some myoepithelial cells. The same localization was less stained for HSP70 and HSP90. The immunocytochemical reaction was weak or negative for HSP110 in striated ducts. HSPs were not expressed in acinic cells. In situ hybridization gave a positive signal in striated ducts with a probe encoding HSP70. Epithelial cells of the striated ducts and myoepithelial cells expressed HSP27, HSP70 and HSP90. These HSPs probably act in part as molecular chaperones for protein synthesis, transport and for several interactions between HSPs and different proteins.     

Secreted heat shock protein gp96-Ig: an innovative vaccine approach

Heat shock proteins (HSPs) are a large family of proteins with different molecular weights and different intracellular localizations. These proteins undertake crucial functions in maintaining cell homeostasis, and therefore they have been conserved during evolution. HSP gp96 also known as glucose-regulated protein grp94, is the primary chaperone of the endoplasmatic reticulum. Gp96/grp94, because of its peptide chaperone capacity and its ability to interact actively with professional antigen-presenting cells (APCs), is also endowed with crucial immunological functions such as natural adjuvant for priming innate and adaptive immunity. To make gp96 accessible to the immune system without biochemical purification and without cell lysis, we generated a secreted form of gp96. The immunological properties of secreted gp96 and its implications for vaccine in human cancer and infectious diseases will be discussed.     

细胞外热休克蛋白70的释放机制及免疫功能

热休克蛋白（heat shock protein，HSP）是机体细胞在受到热应激或其他应激状态下合成增多的一类蛋白质，在细胞的多种功能中起十分重要的作用。最近研究发现，正常人和多种疾病的循环血液和体液中存在热休克蛋白70。而且还发现这种存在于细胞外的热休克蛋白70（extracellular heat shock protein 70，eHSP70）可能作为免疫系统的“危险信号”（danger signal），调节免疫细胞的功能。     

Heat shock proteins and scavenger receptors: role in adaptive immune responses

Tumor-derived heat shock proteins have shown promise as anti-cancer vaccines in clinical trials. Heat shock proteins (HSPs) can generate potent anti-tumor immunity and elicit antigen-specific CD8 + T cell responses in murine studies. Antigen presenting cells (APC), such as macrophages and dendritic cells (DCs), can elicit antigen-specific CD8 + T cell responses mediated by HSPs. CD91 was the first identified endocytic scavenger receptor for HSPs on APC that can facilitate the process of cross-presentation. Other scavenger receptors may also play a similar role in this process. The present review critically evaluates the identified HSP endocytic receptors on APCs that may generate adaptive immune responses. A better understanding of this interaction between HSPs and APCs may further unravel mechanisms of immunoadjuvant function of HSPs.