Current Immunology Reviews (Discontinued) - Volume 2, Issue 3, 2006

Heat shock proteins exert their beneficial effects via basically two modes of action depending on their relative location within the host. Intracellular heat shock proteins found within cells serve a cytoprotective role by chaperoning naïve, misfolded and/or denatured proteins in response to stressful stimuli by a process known as the stress response. However, stressful stimuli also induce the release of intracellular heat shock proteins into the extracellular milieu and circulation. The extracellular heat shock protein serve a cytostimulatory role by initiating immune responses designed to fend off microbial infection and destroy neoplastic transformed cells. This review will briefly cover recent advances into elucidating the mechanism(s) by which stress induces the release of heat shock proteins into the circulation, how it initiates immune responses and suggest the possible biological significance of circulating Hsp to the host.

Macrophage migration inhibitory factor (MIF) describes one of the first cytokine activities to be discovered, but the precise role of this immunologic mediator in the host response only now is being understood. MIF is produced constitutively by diverse cell types, and it circulates normally in the blood at low but immunoregulatory concentrations. Diverse pro-inflammatory or invasive stimuli lead to a rapid upregulation in the release of MIF from pre-formed stores in monocytes/macrophages and other cell types. MIF is necessary for the optimal production of TNF and IL-1, and it upregulates the expression of innate receptors such as TLR-4 and a number of secondary effectors important for innate immunity. Once secreted, MIF has a unique role in inhibiting the activation-induced, p53-dependent apoptosis of monocytes/ macrophages, which is a response that serves to spatially and temporally limit monocyte/macrophage activation responses. This action of MIF results in a necessary but, in certain circumstances, pathologically excessive proinflammatory response. MIF also induces a sustained pattern of ERK-1/2 MAP kinase activation, and it regulates Jab1- mediated transcriptional pathways. Recent studies have identified functional, promoter polymorphisms in the human MIF gene that control its level of expression and that now are being associated with the incidence or the severity of different inflammatory diseases. The different promoter-based MIF alleles appear to exist in a balanced polymorphism that may broadly control innate responsiveness in the human population. These alleles also show significant population stratification, suggesting that the MIF locus may have been subject to different selective pressure over time. The evolutionary persistence of functionally distinct MIF alleles may ensure an essential degree of variation in innate responsiveness for human immunity.

Coxiella burnetii, an obligate intracellular bacterium, causes Q fever, a severe infectious disease. Its high infectivity results in large outbreaks and makes C. burnetii a potential biological weapon. C. burnetii survives within monocytes/ macrophages through a strategy based on the subversion of receptor-mediated phagocytosis and the prevention of phagosome maturation. In addition, the intracellular life of C. burnetii clearly depends on modulation of the cytokine network. This review describes how C. burnetii circumvents the normal trafficking routes from uptake to phagosome maturation and the role of immunoregulatory cytokines on C. burnetii survival in macrophages.

The predominant pathway leading to Major Histocompatibility Complex (MHC) class I presentation of endogenous peptides includes their transport via Transporter associated with Antigen Processing (TAP) molecules. From TAP deficient cells it is, however, known that the ligands of some MHC class I alleles can be presented in a TAP-independent fashion. Professional Antigen Presenting Cells (APCs), which present exogenously acquired peptides, also apply both TAP-dependent and -independent pathways for their MHC class I presentation. TAP-independent pathways for MHC class I presentation of endogenous peptides is interesting for several reasons: Firstly, many virus and tumours specifically inhibit TAP function to avoid immune detection. Secondly, TAP has been shown to be a limiting factor in antigen presentation and it is therefore likely that other "less crowded" routes are more efficient. Thirdly, since the ligands of some MHC class I molecules are poor TAP substrates they need other means of gaining access to loadable MHC class I molecules. When designing epitope-based vaccines, it may therefore prove essential to take the TAP-independent pathways into consideration. In this review we focus on the many different intracellular pathways that have been suggested to lead to TAP-independent MHC class I presentation of endogenous peptides.

Endocrine regulation of the neutrophilic component of innate immunity with a particular focus on the production of reactive oxygen species (ROS) is the subject of this review. Endocrine hormones contribute to neutrophil mediated pathology in several ways either by directly activating the cells, as is the case with an angiotensin activation of NADPH oxidase on neutrophils and monocytes to contribute to atherosclerosis, or by having biphasic effects depending upon the stage of systemic inflammation, i.e. in a hyper-inflammatory phase or a hypo-inflammatory or anergic state, as seen with growth hormone. Some factors, such as a novel anti-inflammatory peptide from salivary glands, the tripeptide FEG, and hypothalamic proline-rich peptide have more subtle effects and appear to negatively regulate the priming events required for neutrophil activation. Investigations on the impact and role of endocrine hormones on neutrophil function and ROS production have contributed to the understanding of the efficacy of some medications in treating inflammation, as is the case with the angiotensin receptor blockers, and should lead to the development of novel drugs that modulate innate immune system function and the severity of an inflammatory response.

Dendritic cells (DC) are the most potent antigens presenting cells with the capacity to stimulate naive T cells and induce primary and secondary immune responses. Due to these features DC have been exploited for vaccine delivery in an attempt to actively immunize cancer patients, but the vaccine- induced immune responses have achieved partial success but are not yet sufficient to attain robust and durable therapeutic effect in cancer patients. The partial failure of current vaccine formulations are explained by the extraordinary complexity of the immune response, which makes the task of exploiting the potential of such a therapeutic approach highly challenging. Overall findings obtained from the clinical observations in human suggest that immune system can be polarized against tumor cells by means of DC mediated vaccine. It is clear that there are complex interactions between tumor cells and DC, through their inhibitory effect on DC tumor cells may negatively regulate priming tumor specific immunity. The complete eradication of tumor is possible only when we gain the thorough understanding of DC biology and its interaction with tumor before we design any vaccine formulations using dendritic cells. This review will summarize the recent advances in understanding the role of DC in the regulation of innate and adaptive anti-tumor immunity, and tumor- induced DC paralysis as a major mechanism by which tumors escape host immune response. Knowledge on these aspects will provide important implications for developing more effective DC mediated vaccination against tumor.

T lymphocytes undergo a complex series of developmental events in the thymus to become mature but naive circulating T cells. These naive T cells are activated during the response to pathogens to produce immune mediators and undergo further differentiation to give rise to distinct types of effector or memory cells. Each of these differentiation and activation events leads to major changes in gene expression patterns. The chromatin structure across a gene is one of the underlying mechanisms that determine its expression level in a specific cell type or in response to an activating signal. The changes in chromatin structure that occur across specific gene loci during differentiation and activation of T cells have been studied in detail in recent years and in many cases, they provide paradigms for the role of chromatin in differentiation and activation in other cell systems. Epigenetic marking and chromatin structure can be viewed as reversible or irreversible states and both appear to play major roles in controlling gene expression patterns in T cells. Reversibility is important for the quick response of cells to their environment, while irreversibility serves to lock in the specific patterns of gene expression that define distinct cell lineages. Changes in the modification state of histone proteins, the strength of histone: DNA contact, the methylation status of the DNA and nuclear location, all serve to determine chromatin structure and accessibility. Here we review the role of chromatin remodelling and epigenetic marking in regulating patterns of T cell gene expression.

Fusions of dendritic cells (DC) and tumor cells are increasingly used in tumor immunotherapy. The strategy for DC-tumor fusion vaccine is based on the fact that DC are the most potent antigen-presenting cells in the body, whereas tumor cells express abundant tumor antigens. The fusion of these two cell types creates a heterokaryon with both DCderived costimulatory molecules, efficient antigen- processing and -presentation machinery, and tumor-derived antigens. In animal and human studies, DC-tumor fusion cells (FC) have been shown to possess the elements essential for processing and presenting tumor antigens to host immune cells and for inducing effective immune response that is able to break T-cell tolerance to tumor-associated antigens; moreover, they have been demonstrated to provide protection against challenge with tumor cells and to regress established tumors. Despite these unique features of DC-tumor fusion cells and the observation of tumor eradication in animal studies, only limited, yet encouraging, success has been seen in clinical trials. This article reviews the methods used for the preparation and selection of DC-tumor fusion cells and analyzes the factors influencing the success or failure of FC-mediated immunotherapy. In addition, it discusses the challenges facing FC vaccine, including preparation, selection, and quality control of DC-tumor fusion cells, and approaches for enhancing antitumor immunity.