Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 2, Issue 4, 2003

Allergic diseases such as asthma, atopic dermatitis, rhinitis and urticaria are immunological disorders, affecting more than 30% of the population in industrialized countries. Advances in the understanding of the molecular and immunological mechanisms of allergic inflammation have identified several new targets that might contribute to new therapies for allergic diseases in the future. Complexity of natural allergen extracts can be recreated using recombinant allergens and hypoallergenic derivates of these are being engineered to increase treatment efficacy and safety. In addition, the use of modern T cell and antigen-presenting cell modulating adjuvants conjugated to recombinant allergens are promising for the future of allergen-specific immunotherapy. T cells are important players in initiating and maintaining the allergic inflammation through release of cytokines, like IL-4, IL-5 and / or IL-13. The blockage of events that are not allergen-specific, such as T cell costimulation and downstream events dependent on IgE, cytokines and chemokines represent important strategies for the treatment of allergy. Nevertheless, all these approaches face the inherent difficulty of attempting to counteract an already established pathological immune response. In addition to the treatment of established allergy, it is essential to consider prophylactic approaches against allergy before initial sensitization has taken place. This article reviews the recent developments in allergen-specific immunotherapy as well as novel agents targeting the immune system in the treatment of allergic diseases.

The immunoregulatory cytokine IL-10 plays a key role in normal and pathological immune responses due to its pleiotropic action on cells of the innate and specific immune system, influencing their differentiation, proliferation and activity. During the immune response an appropriate balance between pro- and anti-inflammatory cytokines, as well as the induction and maintenance of peripheral tolerance are critical. IL-10, mainly produced by antigen presenting and T helper type 2 cells, is engaged in these processes predominantly displaying anti-inflammatory and immunosuppressive properties, but it exerts stimulatory effects as well. The review focuses on the biological activities of IL-10 on cells of myeloid and lymphoid origin and summarizes the current knowledge regarding molecular mechanisms involved in the regulation of IL-10 expression. The pathophysiological role of IL-10 in inflammation and autoimmunity (sepsis, brain-induced immunosuppression, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosis), as well as in allergy and its impact in therapeutic strategies are discussed.

The extravasation of leukocytes from the vascular to the interstitial compartment is a hallmark of the inflammatory response and is associated with the pathogenesis of many cardiovascular and immune-related diseases. Prior to their migration through the vessel wall, leukocytes undergo a series of adhesive interactions that begin as a rolling movement along the vascular endothelium, and are succeeded by stationary firm adhesion to the vessel wall. These rolling interactions are mediated primarily through low affinity interactions via the selectin (E-, L- and P-selectin) family of cell adhesion molecules, whereas firm adhesion between leukocytes and endothelial cells is mediated by the supergene immunoglobulins located on the surface on endothelial cells and their ligands, the integrins (β1, β2), located on leukocytes. The development of monoclonal antibodies and gene-targeted mice aimed at neutralizing these adhesive interactions have become powerful tools in examining the consequences of interfering with leukocyte-endothelial cell adhesion in the progression of many diseases, and validating their inhibition as a therapeutic targets. In recent years, significant efforts in developing small molecule antagonists and protein-engineered inhibitors against the selectins and integrin cell adhesion molecule families have been made. In this review, the available evidence concerning the role of leukocyte-endothelial cell adhesion in mediating vascular dysfunction and tissue necrosis in inflammatory diseases will be examined. Specifically, the development of leukocyte-endothelial cell adhesion inhibitors for the treatment of inflammatory diseases and their therapeutic benefits will be addressed.

Allergen-specific T cells play a pivotal role in initiating and regulating the immune response to allergens, with T cell targeted strategies showing promise for improved specific immunomodulation of the adverse immune response in allergic diseases. Atopic allergic individuals respond to allergen stimulation by dominant secretion of IL-4 and IL-5 (Th2- type cytokines) in contrast to non-atopic individuals where there is predominant IFN-γ secretion (Th1-type). Clinically effective, allergen-specific immunotherapy (SIT) is accompanied by altered allergen-specific T-cell response, notably cytokine changes of decreased IL-4 and IL-5 to IFN-γ ratio (Th2 / Th1) and enhanced IL-10 secretion. Important contributing factors to these changes are likely to include the allergen concentration and form, adjuvants and antigen presenting cell type. Current regimens for SIT using high dose unfractionated allergen extracts injected incrementally via the subcutaneous route are limited by IgE-mediated adverse events, especially in asthmatic patients. Allergen derivatives with retained T cell reactivity but abrogated IgE binding should have higher efficacy and safety. Such derivatives include peptides containing dominant T cell epitopes of allergens and chemically-modified or recombinant mutant allergen molecules. Both approaches have been evaluated successfully in vivo in animal models and limited clinical trials. Th1-inducing adjuvants including bacterial components or virus-like particles, and DNA vaccines may also promote repolarisation of cytokine secretion from Th2-type to Th1-type but caution is needed as excessive IFN- γ secretion may invoke exuberant pathogenic inflammation. Alternative routes for allergen administration including intranasal, oral and sublingual are also under evaluation. Full elucidation of the mechanisms underlying safer, more effective SIT should facilitate wider clinical application in the treatment of allergic diseases and the availability of reliable laboratory assays for monitoring SIT efficacy based on T cell function.

Two closely related zinc metalloprotease (MP) families i.e. MMPs (matrix metalloproteinases) and ADAMs (a disintegrin-like and metalloproteinase-containing protein) including ADAMTSs (ADAMs with one or more thrombospondin domain) have lately become important therapeutic targets in drug discovery research. Although a vast number of MMP inhibitors have been developed in recent years, the results from clinical trials with these compounds have been insufficient for their approval as effective and safe drugs. One of the obstacles to the success MMP inhibitors in clinical development has been the adverse effects caused by undesirable inhibition of non-target MMPs and / or ADAMs. A series of phosphonamide-based compounds recently disclosed by our laboratory includes potent metalloproteinase inhibitors with increased enzyme selectivity relative to the corresponding sulfonamide-based compounds. This increased selectivity arises from the chirality of the phosphonamides core structure, which alters the inhibitor binding mode at the active site of the enzyme. In addition, these phosphonamidebased compounds may be useful for the development of safe metalloproteinase inhibitors, as antedrugs, since phosphonamide structures are known for their instability in the body. This instability may provide a solution to the problem of side effects known to conventional MMP inhibitors and allow new applications for metalloproteinase inhibitors in general.

The classical view of Angiotensin II (AngII), the main peptide of renin angiotensin system (RAS), has changed from a vasoactive agent to a growth factor involved in cell growth and fibrosis and, more recently, to a pleiotropic cytokine, which regulates inflammatory responses. Here, we will review the novel information about the role of AngII as a proinflammatory mediator, and the potential antiinflammatory or immunomodulator effects of RAS blockers. AngII can directly activate immune cells, inducing chemotaxis, proliferation, differentiation and phagocytosis. RAS activation has been observed in inflammatory process and in immune-mediated diseases. Treatment with RAS blockers is a current therapeutic strategy used in human cardiovascular and renal diseases. Their beneficial effects seems due to the blockade of cellular AngII actions, including diminution of proinflammatory parameters. AngII triggers several intracellular signals that participates in the inflammatory response, including production of oxygen radicals, activation of protein kinases and transcription factors, with special attention to the nuclear factor-kB (NF-kB). AngII acts through AT1 and AT2 receptors, however, the receptor involved in the inflammatory process is not fully defined. AT1 is linked to NF-kB activation and upregulation of cytokines, adhesion molecules and chemokines expression. Experimental studies suggest that AT2 / NF-kB pathway participates in inflammatory cell infiltration in the kidney, although its implication in human renal diseases is unknown. Statins possess antiinflammatory and immunomodulatory properties and recent evidence suggest that they could modulate cellular actions of AngII. Although future studies in human diseases are necessary, data present here highlight the importance of AngII modulation in inflammatory and immune processes.

Glucocorticoid receptor agonists are most potent anti-inflammatory agents and indispensable for the treatment of a broad array of inflammatory and immunological disorders. The first compounds introduced into therapy were derived from the natural corticosteroid hydrocortisone. First structural modifications of the core molecule aimed at the increase in selectivity to the glucocorticoid over the mineralocorticoid receptor. Based on a better understanding of structure-activity relationships the next generation of compounds displayed higher receptor affinities and thus higher efficacy. For topically applied glucocorticoids, further progress was achieved by drug targeting, e.g. by inhalation of corticosteroid preparations. Recent developments focussed on the best possible reduction of adverse effects by introducing metabolically labile functional groups into the active molecule to minimize systemic exposure. High affinity to the therapeutic target tissue was recognized as a property that warrants a favorable redistribution kinetics into systemic circulation. These concepts led to a significant improvement of the therapeutic index defined as the ratio of undesired metabolic effects to beneficial antiinflammatory activity for topically applied glucocorticoids. In contrast, no comparable progress has been achieved for systemically administered glucocorticoids yet. However, new insights into alternate pathways of receptor activation suggest the potential for an agonist-driven differentiation between transactivation and transrepression mechanisms. This molecular effector selectivity gives rise to the hope for the development of compounds exhibiting predominantly therapeutically desired effects. This review discusses structure-property relationships of orally and inhalative administered glucocorticoid receptor ligands with steroidal and non-steroidal structure and their translations into clinically observed efficacy and adverse effects.

This article reviews the peripheral benzodiazepine receptor (PBR) and its involvement in inflammatory responses. Diazepam interacts with two distinct receptors. The first one, known as the central-type benzodiazepine receptor (CBR), is associated with the GABA-regulated chloride channel and located in the central nervous system. The second is the peripheral benzodiazepine receptor (PBR) that is found in central as well as various peripheral tissues and that displays pharmacological characteristics distinct from the central type. Indeed, isoquinoline derivatives of carboxamide, such as PK11195, which are high affinity ligands for the PBR, do not bind to the CBR. Diazepam binds PBR and CBR with the same nanomolar affinity, but the 4'-chloro derivative of diazepam, Ro5-4864, binds only the PBR with high affinity. Other benzodiazepines, such as clonazepam and flumazenil, recognise specifically the CBR. The PBR is found on various types of blood cells, mainly monocytes and polymorphonuclear cells (PMN), and PBR ligands modulate monocyte functions, such as chemotaxis, respiratory burst and cytokine secretion. PK11195 and Ro5-4864 strongly inhibit mouse paw oedema formation by carrageenan, exert an inhibitory effect on neutrophil influx and cause a marked reduction in carrageenanstimulated interleukin-13 and interleukin-6 in pleural exudate. PK11195, Ro5-4864 and the recently described, selective PBR ligand, SSR180575 prevent destruction in the joints and limit progression over the articular surface in a model of rheumatoid arthritis. Peripheral benzodiazepine receptor ligands might be of pharmacological interest as potential anti-inflammatory agents.