Novartis Foundation Symposium最新文献

Heat shock proteins (HSPs) play important roles in the immune system as carriers of tumour antigens and inflammatory agents. The HSPs are abundantly expressed stress proteins intrinsic to all cellular life, permitting proteins to carry out essential enzymic, signalling and structural functions within the tightly crowded milieu of the cell. To carry out these tasks, HSPs are equipped with a domain that binds unstructured sequences in polypeptides and a N-terminal ATPase domain that controls the opening and closing of the peptide-binding domain. HSPs can, using these domains, capture antigens processed by partial proteolysis in the cytoplasm of cancer cells. HSP/peptide complexes formed in the cytoplasm can then be secreted to take part in immune surveillance. Extracellular Hsp70 interacts with receptors on antigen presenting cells (APCs) either during episodes of cell death and lysis in vivo or during vaccination. A number of candidate receptors for Hsp70 on APCs have been proposed to take part in the antitumour immune function including the alpha2 macroglobulin receptor CD91, Toll-like receptors, the signalling receptor CD40 and a number of scavenger receptors. Finally, Hsp70 complexes are able to deliver antigens to MHC class I and II molecules on the APC cell surface and lead to the presentation of tumour antigens to T lymphocytes. HSP-antigen complexes have proven effective in the treatment of rodent tumours in preclinical studies and are now undergoing clinical trials for treatment of human cancer.

While there has been a great deal of interest in the role of brain-derived neurotrophic factor (BDNF) in mood disorders and/or the mode of action of antidepressants, less is known about the role of other growth factors. This paper is focused on a group of growth factors, the fibroblast growth factor (FGF) family and their potential role in mood disorders.

Polymorphisms in the Neuregulin 1 (NRG1) and ErbB4 receptor genes have been associated with schizophrenia in numerous cohort and family studies, and biochemical measurements from postmortem prefrontal cortex homogenates suggest that NRG/ErbB signalling is altered in schizophrenia. Moreover, recent work from our group, and from others, indicates that NRG/ErbB signalling has a role in regulating glutamatergic transmission--an intriguing finding given that glutamatergic hypofunction has been proposed to be involved in the pathogenesis underlying schizophrenia. Here we will provide a brief background of the complexity of the NRG/ErbB signalling system. We will then focus on how NRG1 reverses (depotentiates) long-term potentiation (LTP) at hippocampal Schaeffer collateral--CA1 glutamatergic synapses in the adult brain. Specifically, we found that NRG1 depotentiates LTP in an activity- and time-dependent manner. A role of endogenous NRG for regulating plasticity at hippocampal synapses is supported by experiments demonstrating that ErbB receptor antagonists completely block LTP depotentiation by brief theta-pulse stimuli, a subthreshold stimulus paradigm that reverses LTP in live animals. Preliminary results indicate that NRG1-mediated LTP depotentiation is NMDA receptor independent, and manifests as an internalization of GluR1-containing AMPA receptors. The importance of the NRG/ ErbB signalling pathway in regulating homeostasis at glutamatergic synapses, and its possible implications for schizophrenia, will be discussed.

Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 15 years, however, glutamatergic models have become increasingly mainstream, and account for features of the disorder that are poorly explained by dopaminergic dysfunction alone. Glutamatergic models, such as the PCP/NMDA model, are based upon the observation that the psychotomimetic agents phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because NMDA receptors are located throughout the brain, information-processing deficits are observed not only in higher cortical regions, but also in sensory cortices and subcortical systems. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate glutamatergic neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.

Major depression is one of the most common and most debilitating disorders in the world. A wealth of data indicate that additive genetic effects contribute to at least 30% of the variance in liability to major depression, yet attempts to identify the molecular basis of susceptibility using standard family based linkage and genetic association methodologies have had limited success. Alternative approaches have recently been advocated, such as the inclusion of gene by environment interactions and the use of endophenotypes. Our own data indicate that the genetic architecture of affective illness is more complex than expected. A whole genome association study of neuroticism, a personality trait that shares many of the same susceptibility loci as depression, reveals that the individual effect sizes are less than 1%. Larger sample sizes and more sophisticated analytical approaches will be needed than have hitherto been applied.

Mammalian responses to bacterial products can lead to an uncontrolled inflammatory response that can be deadly for the host. It has been shown that the innate immune system employs at least three cell surface receptors, TLR4, CD14 and MD2, in order to recognize bacterial products. We have previously shown that heat shock proteins (HSPs) are also involved in the innate immune recognition. HSPs are a family of highly conserved proteins that act as molecular chaperones and assist in proper folding, assembly and intracellular trafficking of proteins. How HSPs reach the cell surface and how they are involved in the innate immune response still remain unclear. In the present study we investigated their association with the TLR4/CD14/MD2 complex in response to bacterial products and provide evidence that the Hsp70 and Hsp90 associate with TLR4 on the cell surface in response to stimulation by bacterial products. These associations seem to take place within lipid rafts. The addition of exogenous recombinant Hsp70 to cells in vitro results in a dose-responsive inhibition of the inflammatory signal cascade and cytokine production. Our studies reveal that HSPs may play an important role as endogenous regulators of the innate immune response.

Induction of 'adaptive' regulatory T cells (Tregs) using islet-specific antigen vaccinations has been shown to prevent disease in various animal models for type 1 diabetes (T1D). Even though translation from bench to bedside has been unsuccessful so far, this non-invasive approach is the Holy Grail to safely achieve immune tolerance in humans. We will discuss here the fact that every immune response appears to contain a balance of adaptive effector and Treg cells. The evolution of these population and their antigen specificities over time during diabetes development will determine at which time and route a given islet antigen can be chosen to augment such adaptive Tregs most efficiently. Their 'resuscitation' will be crucial for long-term tolerance and homeostasis in the islet micro-environment, which is ultimately needed for a cure from T1D. Recent insight from our studies shows that short-term creation of a systemic milieu that favours Treg propagation, as it occurs after systemic administration of non Fc-binding anti-CD3, can strongly enhance this process. We propose that combination therapies with anti-CD3 or similar systemic immune modulators that lower effector cells and enhance Tregs with vaccines that induce adaptive Tregs will be a crucial step in developing successful immune-based intervention in T1D.

CD8+ T cells are the principal cellular mediators of beta cell destruction in the NOD mouse. Molecular mediators include perforin and granzymes from the cytotoxic granule, Fas ligand and pro-inflammatory cytokines. Our studies in NOD mice have shown that beta cell-specific CD8+ T cells use both the perforin and Fas pathway in vitro. Reducing antigen presentation on beta cells, for example by reducing class I MHC expression by overexpression of SOCS1, protects beta cells in vivo. Perforin deficiency effectively reduces diabetes in NOD mice but in NOD8.3 mice other mechanisms compensate. We have been unable to identify a major role for direct toxicity of cytokines in NOD mice. However, in the LCMV glycoprotein model they may be more important. Deficiency of IL1 or TNF or Fas has a protective effect (greatest for TNF deficiency) but this appears to be due to effects of these cytokines on the immune response rather than on the beta cell. Combinations of interventions, for example, beta cell overexpression of SOCS1 combined with IL1 deficiency may be highly protective. It should be possible to define all the molecular mediators of beta cell destruction, and it may be possible to inhibit at least some of these.

The induction of a cellular stress response was first observed in 1962 in a set of serendipitous experiments in Drosophila melanogasterlarvae, which led to the discovery of a family of intracellular polypeptides known as heat shock proteins (HSPs). These highly conserved proteins are present in both prokaryotic and eukaryotic species, suggesting that they play important roles in fundamental cellular processes. Moreover, these proteins are induced in response to a range of stimuli, implicating HSPs as important modifying factors in an organism's response to a variety of physiological conditions. HSPs were initially regarded as intracellular molecules mediating cytoprotective, regulatory and chaperoning functions. However, the past two decades have seen an explosion of information related to the cell stress response, with a primary focus on molecular chaperones, which are a class of multifunctional intracellular proteins that assist in folding and assembly of other proteins. Stress proteins have also been identified on cell surfaces and in extracellular fluids, and are now viewed as potential immunomodulators, pro-inflammatory signalling molecules, and anti-inflammatory proteins in disease states. This chapter serves as an overview of the rapidly expanding world of cell stress proteins and aims to provide the reader with a foundation for more detailed presentations in subsequent sections of this book.