Inflammation & Allergy-Drug Targets (Discontinued) - Volume 8, Issue 2, 2009

Spleen Tyrosine Kinase (Syk) is widely expressed in the immune system and functions in the transmission of inflammatory signals via ITAM-bearing cell surface receptors. The broad expression pattern and importance of Syk in regulating innate immunity and the inflammatory response have led to significant interest from the pharmaceutical industry to developing anti-Syk therapeutics for the treatment of inflammatory disorders such as allergic rhinitis and rheumatoid arthritis. While the function and regulation of Syk has been well-described in leukocytes, where its primary role is an early transducer of signaling following immunoreceptor engagement, Syk has recently been described in non-immune cells, such as the airway epithelium, that also play an important role in mediating the inflammatory response. This manuscript will focus on the expression and function of Syk in the context of inflammatory lung diseases, and review recent data that have demonstrated novel roles for Syk in airway epithelial cells, particularly its role in mediating the human rhinovirus (HRV) induced inflammatory response and viral cell entry. In addition, data describing the efficacy of novel Syk inhibitors in the management of inflammatory diseases in animal models and early clinical trials are also reviewed.

Allergic rhinitis is a global health problem affecting at least 10 to 25 % of the population. So far, numerious classifications and treatment modalities have been described. In the treatment of allergic disorders Pharmacotherapy is the most used therapeutic modality, especially in allergic rhinitis. The first step to successful management is the accurate diagnosis of the type of AR (intermittent or persistent) and assessment of its severity (mild or moderate to severe). Although objective measurements of the nasal airway have great value to evaluate and follow up the cases, in most centers they are not done in routine clinical practice. Allergen avoidance should be the initial step in the management of AR. Oral antihistamines are the first-line therapy for mild to moderate intermittent and mild persistent rhinitis. They are also recommended for moderate/severe persistent rhinitis cases which are uncontrolled on topical intranasal corticosteroids alone. Corticosteroids are well known for their antienflamatory and anti allergic effects. Topical usage provides topical efficacy while avoiding systemic side effects. Meta-analysis shows that intranasal corticosteroids are superior to antihistamines. They act by suppression of inflammation at multiple points in the inflammatory cascade and reduce all symptoms of rhinitis. A meta-analysis demonstrated that Montelukast was better than placebo, as effective as antihistamines, but less effective than nasal corticosteroids in improving symptoms and QOL in patients with SAR. Good results were reported with subcutaneous and sublingual immunotherapy. Further investigations are promising.

Allergen-specific immunotherapy was introduced into clinical practice at the beginning of the 20th century and its efficacy in the treatment of seasonal allergic rhinitis has been confirmed in many clinical studies which have shown that it can prevent the onset of new sensitizations to different allergens and reduces the development of asthma in patients with allergic rhinitis. Progress in molecular cloning and characterization of allergens have made it possible to produce single recombinant allergens whose immunological properties have been tested in vitro and in vivo and have demonstrated that they retain properties resembling their natural counterpart. Several rational approaches are being developed to improve the efficacy of SIT by reducing immunoglobulin IgE-mediated adverse reactions. Some of these molecules have been tested in the clinic, demonstrating the feasibility of using biotechnology-derived products as new standardized, improved and safer therapeutic compositions.

Human mesenchymal stem cells (hMSCs) are rare progenitor cells present in adult bone marrow that have the capacity to differentiate into a variety of tissue types, including bone, cartilage, tendon, fat, and muscle. In addition to multilineage differentiation capacity, MSCs regulate immune and inflammatory responses, providing therapeutic potential for treating diseases characterized by the presence of an inflammatory component. The availability of bone marrow and the ability to isolate and expand hMSCs ex vivo make these cells an attractive candidate for drug development. The low immunogenicity of these cells suggests that hMSCs can be transplanted universally without matching between donors and recipients. MSCs universality, along with the ability to manufacture and store these cells long-term, present a unique opportunity to produce an “off-the-shelf” cellular drug ready for treatment of diseases in acute settings. Accumulated animal and human data support MSC therapeutic potential for inflammatory diseases. Several phase III clinical trials for treatment of acute Graft Versus Host Disease (GVHD) and Crohn's disease are currently in progress. The current understanding of cellular and molecular targets underlying the mechanisms of MSCs action in inflammatory settings as well as clinical experience with hMSCs is summarized in this review.

Naturally arising regulatory T cells (Tregs) originate from the thymus and are characterised by the expression of Foxp3 as a key control gene for their development and function. Their pivotal role is maintaining immunological self tolerance. Recently, Tregs have been shown to express Toll-like receptors (TLRs), which are essential components of the innate immune system for the detection of microbial infections and the activation of dendritic cells (DC) maturation programs to induce adaptive immune responses. TLRs are type 1 transmembrane receptors characterised by a highly variable extracellular region containing a leucine rich repeat domain (LRR) involved in ligand binding and an intracellular tail containing a highly conserved region, the TIR homology domain, which mediates interaction between TLRs and downstream signalling molecules. Recent data suggest that the activation of TLRs on Tregs can increase or decrease their suppressive activity, thus providing an important link between innate and adaptive immune responses. Treg modulation by TLRs might influence such processes as the response to infections, immune surveillance to cancer, transplant rejection, and the induction of autoimmunity. Understanding the link between Tregs and TLR could be beneficial to the discovery of new therapeutic targets and strategies.

Incidence of autoimmune diseases is rising rapidly in the developed world and treatment of such diseases will be a major burden on Government health resources of the future. Whether systemic or organ-specific, immune cell destruction of the target tissue normally requires co-operative interaction of a many distinct immune cells. Detailed knowledge of the cells and signal pathways involved in tissue destruction is paramount to the design of novel therapeutics. Several organ-specific autoimmune diseases e.g. multiple sclerosis, rheumatoid arthritis and type 1 diabetes have long been attributed to T cell-mediated destruction of the target tissue. However, recent reports from both murine models and man have suggested that B cells are principal players in these T cell-mediated diseases. In this review, we discuss the evidence that supports a link between B cells and the autoaggressive T cell response in type 1 diabetes and how accumulating evidence suggests targeting B cells may offer a novel therapeutic strategy for this autoimmune disease.

Juvenile idiopathic arthritis (JIA) is a group of chronic childhood arthritides of unknown origin. Although the use of glucocorticoids and immunosuppressants brought a substantial improvement in treatment, the present therapeutic regime could not be considered satisfactory. As inflammation seems to be an essential part of pathogenesis of JIA, efforts have been made to develop pharmaceutical means to mitigate the innate immune system. Emerging targets for treatment are alarmins, a family of multifunctional intracellular proteins with strong pro-inflammatory activity. In the context of JIA, particularly interesting are high mobility group box 1 (HMGB-1) and three members of the S100 family: S100A8, S100A9, and S100A12. No definite conclusion can be made at the time, but both animal models and clinical studies support the concept of alarmins as possible key mediators of JIA. Therefore, pharmacological interference with alarmin pathways could turn out to be an excellent strategy for long-term management of JIA. Several options have been tested and they either inhibit the release of alarmins or sequester the already secreted ones. Although still very few in number, therapeutic experiments on mice are quite optimistic. Thus, it was the purpose of the present review to give an overview of the present knowledge on the topic and to bring this exciting new therapeutic possibility to the focus of rheumatologists.

The CLCA proteins were first shown to exist in bovine trachea and named as chloride channels calcium activated (CLCA) due to the calcium-dependent chloride conductance that appeared to be activated on expression of these proteins in trachea and other secretory epithelial cells. Since their initial discovery the CLCA gene family has grown extensively and family members have been identified in bovine, human, murine, equine and porcine tissues. The CLCA proteins appear to have a role to play in chloride conductance across epithelial cells and hence epithelial fluid secretion; cellcell adhesion, apoptosis, cell cycle control and tumorgenesis and metastasis; mucous production and cell signalling in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). There are four human homologues; hCLCA1, hCLCA2, hCLCA3 and hCLCA4. Interest in these proteins has gathered pace with the description of hCLCA1's involvement in several human respiratory diseases. This review will describe the CLCA gene family and then move on to look at the growing body of evidence that suggests that at least hCLCA1 has an important role in the pathogenesis of respiratory disease such as asthma, COPD and cystic fibrosis (CF).

Tolerance induction is a fascinating option to prevent allergic diseases or allograft rejection. Calcitriol is the hormonal form of vitamin D and is produced by two hydroxylation steps: a hepatic 25-hydroxylation of vitamin D and a subsequent renal 1α-hydroxylation. Calcitriol has important immunomodulatory properties. Calcitriol can prevent those inflammatory processes which are responsible for allograft rejection, whereas its effects on immunological responses related to allergic reactions are more complex and not fully elucidated. This article summarizes present knowledge on vitamin D and the adaptive immune system. Experimental and clinical studies support the assumption that calcitriol can decrease the risk of allograft rejection. Prospective randomized clinical trials are however needed to clarify whether administration of calcitriol, some of its analogues, or simple vitamin D supplementation is able to prevent rejection in solid organ transplanted patients. With respect to allergic reactions, human data are inconsistent at present. Some argue that vitamin D deficiency may cause allergic reactions whereas others argue that vitamin D excess leads to an increased allergy risk. In this context, current strategy of vitamin D supplementation in infants and the possibility of a bimodal effect on allergic reactions of both, vitamin D deficiency and excess are discussed.