Endocrine, Metabolic & Immune Disorders-Drug Targets - Volume 9, Issue 4, 2009

Under normal physiological conditions there is minimal entry of immune cells into the central nervous system (CNS) for the purpose of immune surveillance. During inflammation, however, extensive infiltration of immune cells can lead to the induction of CNS autoimmune disease, for example multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The barriers that regulate cellular entry are the blood-brain barrier (BBB) within the CNS parenchyma, and the blood-cerebrospinal fluid (blood-CSF) barrier within the choroid plexus. Understanding how these barriers function to allow the passage of leukocytes from the periphery into the CNS for normal immune surveillance, and under inflammatory conditions, is vital for the development of novel therapeutics targeting immune cell migration in CNS diseases. Contributions from selectins, chemokines, integrins and matrix metalloproteinases allow the migration of leukocytes across the BBB and into the CNS parenchyma. In EAE and MS, the strict maintenance of this process is lost and a large influx of cells is seen. This review focuses on the role of these homing molecules, chemokines and enzymes in the entry of leukocytes into the CNS during inflammatory conditions. It concludes with a model of immune cell entry of the CNS, summarising the current knowledge in this area. Targeting specific molecules to prevent infiltration of inflammatory cells into the CNS could allow disease inhibition without compromising beneficial immune surveillance.

Tumour immunotherapy has become a treatment modality for cancer, harnessing the immune system to recognize and eradicate tumour cells specifically. It is based on the expression of tumour associated antigens (TAA) by the tumour cells and aims at the induction of TAA-specific effector T cell responses, whilst overruling various mechanisms that can hamper the anti-tumour immune response, e.g. regulatory T cells (Treg). (Re-) activation of effector T cells requires the completion of a carefully orchestrated series of specific steps. Particularly important is the provision of TAA presentation and strong stimulatory signals, delivered by co-stimulatory surface molecules and cytokines. These can only be delivered by professional antigen-presenting cells, in particular dendritic cells (DC). Therefore, DC need to be loaded with TAA and appropriately activated. It is not surprising that an extensive part of DC research has focused on the delivery of both TAA and activation signals to DC, developing a one step approach to obtain potent stimulatory DC. The simultaneous delivery of TAA and activation signals is therefore the topic of this review, emphasizing the role of DC in mediating T cell activation and how we can manipulate DC for the pill-pose of enhancing tumour immunotherapy. As we gain a better understanding of the molecular and cellular mechanisms that mediate induction of TAA-specific T cells, rational approaches for the activation of T cell responses can be developed for the treatment of cancer.

T cell immunity is critical for a protective immune response against cancers. Traditionally, this function has been ascribed to CD8 T lymphocytes with cytotoxic activity, which are restricted by MHC class I molecules. The lack of direct cytolytic effector function on part of CD4 T cells, which are MHC class II restricted, coupled with the MHC class II negative nature of most human cancers have been the main reasons for CD8 centered cancer immunotherapy approaches, so far. However, recent findings showing that CD4 T cells play an essential role towards the generation of a productive CD8 response and that the CD4 T cells can also play a direct role in anti-tumor immunity have resulted in growing enthusiasm towards engaging CD4 T cells in cancer immunotherapy. We here discuss the current approaches used for immune based cancer therapy, role of natural MHC class II-restricted CD4 T cells in tumor immunity, factors limiting the engagement of natural CD4 T cells in cancer immunotherapy protocols alongside CD8 T cells, and recent advances in TCR engineering approach to address these limitations. We will also discuss the significance of the MHC class I directed antitumor CD4 T cells in tumor immunity.

The gene encoding Melanoma-differentiation antigen-7 (MDA-7) was discovered more than 10 years ago. Its potential anti-cancer activity was surmised because its expression is inversely correlated with the cell proliferation status. Indeed adenoviral delivery of this gene proved to be efficient in killing several cancer cell lines and great strides have been made concerning its molecular ways of action. Later it was shown that mda7 encoded a secreted cytokine which belongs to the IL-10, class-II family of cytokines. We recently found that this molecule exerted apoptotic activity on stimulating but not on resting lymphocytes from a B cell leukaemia. This activity is distinct from that of intracellular MDA-7, and may pave the way for using the cytokine in cancers provided that they express the IL-24 Receptors; in this respect, melanomas are insensitive to the recombinant cytokine due to the lack of IL-24 receptors at their surface. In contrast to its anti-cancer activity, the immunological role of IL-24 is still unclear, with differences between mice and human. If however it is demonstrated that IL-24 can inhibit the function of STAT3 in normal lymphocytes as it is the case in leukemic cells, and given that STAT3 is needed for the differentiation of several lymphocyte subsets, this will give us hints as to the potential role of this cytokine in the immune system.

Accumulating evidence demonstrates that bacterial chemoattractants not only attract leukocytes (chemotaxis) but also contribute directly to inflammation by activation of leukocytes to produce a variety of pro-inflammatory cytokines. Recent studies have shown that mixtures of the bacterial chemoattractant fMLP (N-formyl-Met-Leu-Phe) and other bacterial products/components such as LPS (lipopolysaccharide) behave synergistically in activating leukocytes. These results suggest that inflammatory responses are induced by multiple inducers that operate synergistically through multiple signaling pathways. This synergy is likely to play a significant role in the induction of host defense to bacterial infections and in the pathogenesis of inflammatory disorders. These results also demonstrate that the control of inflammation is likely best understood at the level of synergistic regulation of intracellular signaling. The use of pharmacological inhibitors to modulate synergistic molecules is therefore an attractive possibility for the treatment of inflammatory disease. In this review, we will provide a brief summary of recent studies on the regulation of leukocyte functioning by bacterial chemoattractants.

Anti-resorptives that prevent osteoclasts from resorbing bone are the mainstay of treatment for osteoporosis, while parathyroid hormone is the only agent available that stimulates osteoblasts to form bone. Advances in knowledge about metabolic pathways in bone cell biology have identified specific points of intervention whereby formation and function of osteoclasts and osteoblasts can be inhibited or stimulated. The next generation of therapies for osteoporosis may include molecules that antagonize integrin or inhibit Src tyrosine kinase, vacuolar H+-ATPase, chloride channel or cathepsin K, thus preventing osteoclasts from attaching to bone, form a ruffled border, acidify resorption lacunae or digest organic bone matrix. At least some of these may form a novel class of anti-resorptives capable of inhibiting bone resorption without being coupled to inhibition of bone formation. Human and mouse genetics studies demonstrating the pivotal role of the Wnt signaling pathway in bone metabolism have led to the development of strategies to disrupt Wnt signaling in order to increase bone formation. Selective androgen receptor modulators that produce an anabolic effect on muscle and bone without undesirable androgenic side effects can potentially be used to treat osteoporosis, aged-related frailty, muscle wasting disorders and glucocorticoid-induced osteoporosis. Studies involving these molecules are still in either preclinical or early investigational stage, without fracture data. Nonetheless, preliminary results hold the promise that at least some of these new therapies may develop into effective means of treating and preventing osteoporosis. Any new therapy for osteoporosis must take into consideration its safety, efficacy, affordability and specificity of action.

Over the past decades, the paradigm that lysosomal enzymes participate only in non-specific protein degradation during cell death has changed. Studies conducted both in cell cultures and in animals defined the role of these enzymes that includes cathepsin D (CD). Knockout mice revealed the role of CD in postnatal tissue homeostasis and remodeling. Mutations that abolish the CD enzymatic activity have been implicated in neural ceroid lipofuscinosis. Recent studies suggested a differential role of CD in regulation of apoptosis. The zymogen of CD, procathepsin D (pCD), is secreted by various cancer cells. Extensive studies showed that it acts as a mitogen on both cancer and stromal cells by stimulating their invasive and metastatic properties. Additional studies suggested that procathepsin D/CD is an independent prognostic factor in various cancers, leading to the investigations of pCD/CD as a potential target for designing anti-cancer therapy. In this review, we described the various forms of CD and their implications in numerous physiological as well as pathological conditions.

Type 2 Diabetes Mellitus (T2DM) which is characterised by insulin resistance, is closely linked to the triad of glucolipotoxicity, inflammation and oxidative stress. Increased adiposity, leading to increased free fatty acids (FFAs), contributes to insulin resistance by disrupting the signal transduction pathway of insulin mediated glucose disposal, and causes impaired insulin secretion. Hyperglycaemia and dyslipidaemia driven oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defence is implicated in the pathogenesis of diabetic neuropathy (DN). This and other inflammatory pathways account for a complex network of interacting metabolic factors responsible for causing diabetes and her complications. There is growing evidence that Alpha Lipoic Acid (ALA) has beneficial effects on the treatment of T2DM and some of its complications. It represents an attractive pharmacological target in the treatment of T2DM by modulating the signal transduction pathways in insulin resistance and antagonizing the oxidative and inflammatory stresses, which are major players in the pathogenesis of this disorder. A potent anti-oxidant and free radical scavenger, ALA also targets cellular signal transduction pathways which increases glucose uptake and utilization, thus providing specific targeted therapy in the treatment of insulin resistance and diabetic neuropathy. Apart from the rare risk of Insulin Autoimmune Syndrome (IAS), ALA has shown to be relatively safe, even in patients with renal and liver failure. This review focuses and summarises the molecular mechanisms of T2DM, and underlines the therapeutic value of ALA in this globally significant disease.