Current Drug Targets – Inflammation & Allergy, Vol. 1, No. 1, 2002

Bronchial asthma is not a homogenous disease. Several variants of asthma can be distinguished. One of them is aspirin-induced asthma. In this distinct clinical syndrome, aspirin and most other nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase-1 precipitate rhinitis and asthma attacks. This type of asthma affects 5-10% of adult asthmatics, but remains largely underdiagnosed. The natural history of aspirin-induced asthma (AIA) has been described, based on an extensive pan-European survey. Aspirin provocation tests with improved diagnostic accuracy have been developed, although no in-vitro tests has been found to be of diagnostic value. Recent interest in AIA has been stirred by the finding of alterations in arachidonate metabolic pathways, leading to cysteinyl-leukotriene overproduction. LTC4 synthase is overexpressed in bronchi and its mRNA is upregulated in peripheral blood eosinophils. The gene coding for LTC4 synthase exists in two common alleles, one of which appears to be associated with a severe, steroid-dependent type of asthma. New highly specific COX-2 inhibitors appear to be a safe alternative for patients with aspirin-induced asthma.

[Back to top] Leptin as a Novel Therapeutic Target for Immune Intervention

G. Matarese, V. Sanna, S. Fontana and S. Zappacosta

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The recent cloning of the leptin (obese, ob) gene has determined fundamental insight into the understanding of the regulation of food intake, basal metabolism and reproductive function. Leptin, mainly secreted by adipocytes, belongs to the helical cytokine family and its plasma concentrations correlate with fat mass and respond to changes in energy balance. Initially, leptin was considered as an anti-obesity hormone, but experimental evidence has also shown pleiotropic effects of this molecule on hematopoiesis, angiogenesis, lymphoid organ homeostasis and T lymphocyte functions. More specifically, leptin links the pro-inflammatory T helper (Th)-1 immune response to the nutritional status and the energy balance. Indeed, decreased leptin concentrations during conditions of food deprivation lead to impaired immune capabilities. This review focuses on the potential therapeutic utilities for agents that manipulate the leptin-adipocyte axis and discusses novel strategies for an immune intervention in pathologic conditions.

[Back to top] 5-Lipoxygenase: Cellular Biology and Molecular Pharmacology

Oliver Werz

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5-Lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes, proinflammatory mediators which are mainly released from myeloid cells. Whereas LTB₄ is a potent chemotactic and chemokinetic agent for a variety of leukocytes, the cysteinyl-leukotrienes C₄, D₄ and E₄ cause vascular permeability and smooth muscle contraction. In view of these properties, leukotriene synthesis inhibitors have been hypothesized to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. Whereas cysteinyl-leukotriene receptor antagonists possess potential for antileukotriene therapy in asthma, results from clinical trials with leukotriene synthesis inhibitors were less encouraging.

The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxides; nevertheless activation of cellular 5-LO in response to external stimuli is rather incompletely understood. Intensive research revealed that on cell stimulation, 5-LO redistributes to the nuclear membrane where it colocalizes with 5-lipoxygenase-activating protein and cytosolic phospholipase A₂ . In addition, various cellular proteins interacting with 5-LO have been identified. It was suggested that enzyme phosphorylation could influence redistribution and cellular activity of 5-LO and that the cellular redox tone regulates 5-LO product formation. This review highlights the determinants of cellular 5-LO activity and summarizes the molecular pharmacology of 5-LO.

[Back to top] Oral Tolerance in the Treatment of Rheumatoid Arthritis

Éric A. Toussirot

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Oral tolerance (OT) consists of the oral administration of antigens (Ag) that could alter the response of the immune system. This is a form of peripheral immune tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered non fonctional or hyporesponsive by prior oral administration of Ag. It was first described in 1911 in animal models of anaphylaxis. This therapeutic approach requires the orally administration of Ag and the active participation of the gut-associated lymphoid tissue (GALT), a tissue comprising Peyer’s patches, intraepitelial cells and villi containing epithelials cells which is a well organized immune network.

The mechanisms by which OT is mediated included deletion or anergy and active cellular suppression. The primary factor determining which form of tolerance will be developed after oral administration of Ag is the Ag dosage. Thus, it is thought that low doses of Ag induce the generation of active suppression, via regulatory T cells in the GALT, which then migrate to the systemic immune system. These regulatory T cells produce down-regulatory cytokines such as IL4, IL10 and TGFb, a Th2 / Th3 cytokine pattern. Conversely, high dose of Ag favors anergy or clonal deletion. The phenomenon in which regulatory cells, as generated by oral tolerization, are primed in an Ag specific manner, but act in the respective microenvironment in a non-Ag specific manner is called bystander suppression. This phenomenon is of particular interest and explained the use of OT in T cell mediated autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type I diabetes, some diseases in which the autoAg remains unknown or where there are reactivities to multiple autoAgs.

There were several studies demonstrating the effectiveness of orally administered Ag in different animal models of autoimmune diseases, such as experimental allergic encephalomyelitis, collagen induced arthritis, diabetes, but also uveitis, myastenia gravis and transplantation. These mouse or rat models of autoimmune diseases gave the rationale for the therapeutic use of OT in human and this therapeutic approach has been tried in MS and RA, using oral myelin or oral collagen, respectively. In RA, 4 trials of oral type II collagen (CII) in RA have been published. Taken together, these studies suggested that oral CII in RA gave a trend toward clinical improvement, with significance in only 2 studies. Bacterial extract from Escherichia coli containing heat shock proteins has been tried in oral treatment for RA. Two placebo controlled trials and 2 comparative studies gave favorable results for this bacterial extract with no or mild adverse events.

Altough oral/mucosal tolerance has given successful results in animal models of autoimmune diseases, the enthusiasm for this therapeutic approach in human diseases must be tempered. The discrepancies between the effectiveness of OT in animal models and the resullts in human trials raise some questions, the identification of the subgroup of patients who might respond to this treatment and the source (or nature) of the administered Ag (homologous versus heterologous), for instance.

[Back to top] Endocannabinoid Degradation, Endotoxic Shock and Inflammation

M. Maccarrone, M. Bari, N. Battista and A. Finazzi-AgrÒ

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Endocannabinoids are an emerging class of lipid mediators, which include amides and esters of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors. Endotoxic shock is a potentially lethal failure of multiple organs that can be initiated by the inflammatory agent lipopolysaccharide (LPS), present in the outer membrane of gram-negative bacteria. LPS has been recently shown to stimulate the production of AEA in rat macrophages, and of 2-AG in rat platelets. The mechanism responsible for this effect has not been elucidated. On the other hand, mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play an essential role in inflammation. As yet, little is known about endogenous modulators and mechanisms of mast cell activation. Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH). We also report the ability of the HMC-1 human mast cells to degrade AEA through a nitric oxide-sensitive AMT and a FAAH. The role of endocannabinoids in HMC-1 degranulation is discussed as well. Taken together, it can be suggested that human lymphocytes and mast cells take part in regulating the peripheral endocannabinoid system, which can affect some activities of these cells.

[Back to top] An Update of Immunotherapy for Specific Allergies

Susan L. Prescott and Catherine A. Jones

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Allergic diseases are common, disabling and potentially life threatening. The processes that lead to production of excessive allergen-specific IgE production are highly complex and heterogeneous. While current treatment strategies are limited, recent technological advances have provided a better understanding of underlying disease processes and offered new potential therapeutic targets. Optimal treatment strategies permanently modify underlying inflammatory allergic immune responses (immunotherapy) with long term alleviation of symptoms and minimal side -effects. Although these processes are still not completely understood, methods of modifying allergen recognition by the immune system have already been successful. Here, we review recent developments and future directions in allergen immunotherapy and adjunctive therapies. Specifically, we address the molecular mechanisms of allergen immunotherapy and new techniques including allergen modification, allergen gene vaccination, CpG immunostimulation, and peptide immunotherapy. Other non-allergen specific molecular targets (including receptor, cytokine and IgE targets) which may complement specific immunotherapy are also discussed. Ideally these methods will eventually be replaced by strategies targeting the prevention of allergic responses (immunoprophylaxis).

[Back to top] The Immunosuppressive Activity of Proinflammatory Cytokines in Experimental Models: Potential for Therapeutic Intervention in Autoimmunity

U. Grohmann and P. Puccett

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The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory/immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.

[Back to top] Inducible Nitric Oxide Synthase – Time for Reappraisal

Philipp Lirk, Georg Hoffmann and Josef Rieder

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Inducible nitric oxide synthase (iNOS) is one of three key enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in numerous physiological and pathophysiological conditions, e.g. blood pressure regulation, inflammation, infection, and the onset and progression of malignant diseases. iNOS has been conjectured both as a marker and a therapeutic target in these situations.

iNOS is a mediator of unspecific host defence, central in the clearance of bacterial, viral, fungal and parasitic infections. However, excess production of NO appears to be linked to tissue damange and organ dysfunction, e.g. the hypotensive and vasoplegic state characteristic for septic shock. However, the use of iNOS-inhibitors in septic patients should be performed carefully with regard to the essential functions and properties of NO in blood pressure/blood flow regulation.

Considering iNOS-derived NO as a multifactorial transmitter of tumorigenesis and tumor progression, it is tempting to speculate on therapeutical interference with iNOS activity, especially in tumors where metastatic activity, host denfence mechanisms and the level of differentiation seem to be correlated to iNOS expression.

It is the aim of this review to provide basic insights into the NOS family of enzymes as well as their regulation. In the second part of the review, we will point out the pivotal roles NOS play in inflammation and neoplastic diseases.

[Back to top] Chemokines in Allergy

David Chantry and Laurence E. Burgess

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Allergic diseases such as atopic dermatitis, asthma, and allergic rhinitis represent a significant healthcare problem. Understanding these diseases as dysregulated inflammatory responses has led to many new targets for therapeutic intervention. Recent data concerning soluble IL-4 receptor, monoclonal antibodies against IL-5 and an antibody toward IgE have lead to an appreciation of the crucial role played by Th2 subset of CD4⁺ T cells and their corresponding cytokines. While these potential drugs are presently in clinical trials and may be valuable therapeutics, orally bioavailable small molecule inhibitors of Th2 cell responses would be desirable for treatment of these chronic diseases. One strategy is to prevent effector cell migration (Th2 cells, mast cells, and eosinophils) via chemokine receptor antagonism with a suitable small molecule.

Chemokine receptors are a subset of the seven transmembrane-spanning family, which mediate their effects through interaction with heterotrimeric G-proteins. The ligands are a structurally related set of proteins that are selectively expressed in certain disease settings. Three chemokine receptors CCR3, CCR4, and CCR8 are preferentially expressed by Th2 cells, mast cells and eosinophils and therefore represent therapeutic targets for allergy.

This mini-review will focus on new research involving CCR3, CCR4 and CCR8. The cellular distribution of each receptor, the corresponding chemokine ligands, and various validation studies are discussed. Recent drug discovery advances concerning pharmacological tools and small molecule receptor antagonists will also be presented.

[Back to top] Mode of Action of Long-Term Low-Dose Macrolide Therapy for Chronic Sinusitis in the Light of Neutrophil Recruitment

Hideaki Suzuki and Katsuhisa Ikeda

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Chronic sinusitis is a common inflammatory upper respiratory tract disease. One of the prominent features of this disease is persistent purulent effusion containing numerous emigrated neutrophils in the paranasal sinuses. Recent advances in sinusitis research have revealed two positive feedback mechanisms that explain the chronic neutrophil accumulation in the sinus. First, interleukin (IL)-1b secreted by monocytes, macrophages and fibroblasts upregulates the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial cells, and thereby induces the extravascular transmigration of neutrophils. The emigrated neutrophils then secrete IL-1b, which amplifies the expression of E-selectin and ICAM-1, resulting in further neutrophil infiltration. Second, chemoattractants including IL-8 in the sinus effusion initiate neutrophil exudation. Emigrated neutrophils then secrete IL-8, which elicits further neutrophil accumulation in the sinus effusion.

Long-term low-dose macrolide therapy was first introduced for the treatment of diffuse panbronchiolitis in the 1980's. In the 1990's it was also shown to be an effective treatment for chronic sinusitis. The inhibitory effect of macrolides on neutrophil infiltration in inflammatory sites has been well documented in these diseases. Several lines of evidence indicate that macrolides do not function simply as a bactericide. In vitro studies have demonstrated various effects of macrolides on immunocompetent cells, inflammatory cells and airway epithelial cells. It has been shown that macrolides inhibit the production of IL-8 and IL-1b and the expression of ICAM-1, suggesting that macrolides block the aforementioned dual positive feedback system of neutrophil recruitment and thereby exert their clinical efficacy in the treatment of chronic sinusitis. The inhibitory effects of macrolides on multiple steps in the process of neutrophil recruitment are presumably mediated by the inhibition of transcription factors such as nuclear factor-kB and activator protein-1. Further investigation of the mode of action of macrolides at the molecular level would lead to the development of safer and more effective drugs for the treatment of chronic sinusitis. In addition, the possible risk of this therapy such as the occurrence of resistant strains have to be carefully surveyed hereafter.

Current Drug Targets – Inflammation & Allergy, Volume 1, Number 1, 2002

Contents

Abstracts

U. Grohmann and P. Puccett

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Hideaki Suzuki and Katsuhisa Ikeda

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