Inflammation & Allergy-Drug Targets (Discontinued) - Volume 7, Issue 1, 2008

Derived from the historical molecule sulfasalazine, mesalamine has remained one of the mainstays for treatment of inflammatory bowel disease in the last 50 years. Recent advancement in both clinical and basic research has led to reappraise the drug under two crucial aspects. Firstly, there has been a re-evaluation of the chemo-protective effect of mesalamine against sporadic colorectal cancer. Evidence that inflammation plays a strong role in tumor induction from one side, and demonstration that mesalamine can touch on specific molecular steps enhancing apoptosis on the other side have re-shaped the indications of mesalamine for ulcerative colitis. Secondly, the role of thiopurines (azathioprine and 6-MP) in the maintenance of remission of ulcerative colitis has been reiterated by the results of several clinical trials. During attempts at clarifying the reasons why certain patients appear to be resistant to thiopurines, it was interestingly found that mesalamine can interfere thiopurine metabolism, causing an increased blood concentration of the specific immunosuppressive metabolites and a sequential enhancement of drug effectiveness. Mesalamine is therefore being studied as a means to overcome the genetically determined resistance to thiopurines. Such sharpened indications have reiterated attention to correct dosing: the results of controlled trials have shown mesalamine to be fully effective at twice the traditional daily dosage (4.8 grams instead of 2.4). The attendant problems of compliance seem to find solution in the availability of multi-matrix system formulations. This mesalamine story reminds us that in the absence of an etiological target capable to guide research to trace one abrogating molecule, (as it has happened for viral hepatitides for example), treatment of inflammatory bowel disease remains anti-inflammatory in nature and thus multifaceted. Besides justified use of cutting-edge technology to find novel molecules, smart re-evaluation of what is already in our hands can sometimes bring about unexpected breakthroughs.

In recent years it has become apparent that the liver holds a distinct immunological position. Previously described as a “graveyard” for T cells activated in the periphery, emerging evidence indicates that this organ may have a more active role in mediating tolerance. Attenuated immune responses in the liver can be beneficial in the transplantation setting, as liver transplants are more readily accepted than other organ allografts even in the absence of immunosuppressive drugs. However, the ability of the liver to induce immunological unresponsiveness could be exploited by some pathogens, such as the hepatitis C virus (HCV), to establish chronic infections with potentially fatal outcomes. Understanding the mechanisms controlling the balance between intrahepatic tolerance and immunity is critical in order to design new strategies to enhance acceptance of solid organ allografts and to promote efficient immune responses against HCV. In this article, we will review current knowledge of the mechanisms regulating intrahepatic immunity and discuss how these mechanisms might potentially be targeted to achieve advantageous clinical outcomes in transplantation and persistent hepatotropic infections.

A bidirectional relation between depression and natural immunity has been identified: depressive episodes are associated to a relative immunodeficiency, conversely inflammatory activity has been implicated in the development of depressive symptoms and in the pathophysiology of depression. Depression has been associated with a decrease in the number and activity of NK lymphocytes and hence patients with depression may show immunodeficiency towards intracellular microorganisms and tumors. Paradoxically, depression is sometimes accompanied by an inflammatory state, developed from the peripheral stimuli (atopy) or central stimuli (chronic stress) and mediated by proinflammatory cytokines (IL-6, TNF and IL-1). These cytokines can play a role in the pathophysiology of depression and of various diseases, supporting the hypothesis that many chronic diseases are individual manifestations of a common proinflammatory denominator.

Transglutaminases (TG, E.C. 2.3.2.13) are a family of related and ubiquitous enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other reactions which are important for cell life. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the pathogenetic mechanisms responsible for several human diseases. In particular, “tissue” TG (tTG, type 2), a member of the TG enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD), which is characterized, in part, by aberrant transglutaminase activity and by the presence of transglutaminase-modified proteins. In this review we describe the biochemistry of TGs, with particular reference to the molecular mechanisms involved in the physiopathology of this human disease, as a model for the study of other immunological disorders.

Mucus hypersecretion is common in inflammatory and allergic lung disease. Excessive mucus production leads to obstruction of airways and favours bacterial colonization. Advances in understanding the signalling and transduction pathways of mucin gene expression as well as mechanisms of mucin protein production and secretion have defined new therapeutic targets. Conventional therapies include anticholinergics, β2-adrenoceptor agonists, glucocorticosteroids, mucolytics and macrolide antibiotics. Novel therapeutic approaches are inhibitors of cholinergic nerve activity, tachykinin receptor antagonists, epoxygenase inducers, inhibitors of mucin exocytosis, inhibitors of mucin synthesis and goblet cell hyperplasia, inducers of goblet cell apoptosis and P2Y2 purinoceptor antagonists to inhibit mucin secretion. After providing a short overview on conventional therapies this review will focus on new therapeutic targets.

Structurally-unrelated immunosuppressive drugs, cyclosporin A and FK506 (tacrolimus), that share a common intracellular target protein, calcineurin, display strong and similar efficacy in the cases of organ transplantation and other immunological diseases. However, prolonged use of these drugs in many chronic diseases is restricted due, at least in part, to their side effects. The pharmacological effects of cyclosporin A and FK506, represented by the suppression of T cell activation and proliferation, are exhibited via inhibiting the activity of a transcription factor, nuclear factors of activated T cells (NFAT). The NFAT family members are involved in inducible expression of numerous genes concerned with immune responses as well as other biological events. Studies using gene-targeted mice have suggested that each NFAT family member plays a differential role in the synthesis of multiple cytokines. The diversity of the NFAT family is one of the reasons for the potent and wide-variety of side effects induced by cyclosporin A and FK506. However, molecular mechanisms underlying the functional differences among the NFAT family have not been fully elucidated. We have been investigating the comparative roles of NFAT members in regulating T cell cytokine synthesis. In addition, in order to identify the essential region in NFAT responsible for the specificity of individual NFAT members, we have applied a novel assay technique to accurate assessment of interacting properties between NFAT and its binding partners. This article summarizes the potential and possibility of selective NFAT inhibitors in the treatment of immunological and inflammatory diseases with introducing our recently elucidated findings.

Transferrin (Trf) is a highly conserved serum glycoprotein mostly known for its iron transport capacity. As iron is an indispensable nutrient for cell division, Trf and its receptor have long been used as targets of pharmacological intervention mostly for cancer therapy and for diagnosis in inflammation. In recent years several independent pieces of work including data from our group, indicated that Trf can also have an iron independent role in the immune system. In this article new emerging roles of Trf and its receptor on iron independent processes and in drug delivery are reviewed.

Rheumatoid arthritis (RA) is a multifactorial disease characterized by chronic inflammation of the joints. Both genetic and environmental factors are involved in the pathogenesis of joint destruction and disability. In the inflamed RA joint, the synovium is highly infiltrated by CD4+ T cells, B cells, and macrophages. Furthermore, the intimal lining becomes hyperplastic due to the increased numbers of macrophage-like and fibroblast-like synoviocytes. This hyperplastic intimal synovial lining forms an aggressive front, called pannus, which invades cartilage and bone structures, leading to compromised function and/or destruction of affected joints. RA pathology is mediated by a number of cytokines (TNF-α, IL-1, IL-6, IL-17, IFNγ, etc.), chemokines (MCP-1, MCP-4, CCL18, etc.), cell adhesion molecules (ICAM-1, VCAM-1, etc.) and matrix metalloproteinases. Currently, treatment strategies targeted against TNF-α, IL-1 and IL-6 are available. In this review, we will summarize the use of biologics, the pros and cons of the use of biologics, and discuss on the potential molecular targets of RA.