Inflammation & Allergy-Drug Targets (Discontinued) - Volume 7, Issue 3, 2008

Inflammatory bowel disease (IBD) is a progressive condition in gastrointestinal tract, which refers to two idiopathic diseases; ulcerative colitis and Crohn's disease. Although certain etiology of these conditions is not known, it seems that an abnormality in reaction and regulation of the immune system plays an important role in adventure of the disease. According to the investigations, it is likely that oxidative and nitrosative stress have etiologic roles in IBD. Their destructive effects may contribute to the initiation or progression of the disease. Nowadays, the effectiveness of different medicines in the treatment of IBD has been proved, but none of them has shown a desirable result. Potassium channel openers (PCOs) are a class of drugs with various usages in the aspects of cardiovascular diseases and urinary incontinence. Their major mechanism is the opening of ATP-sensitive potassium (K-ATP) channels and contribute to the relaxation of smooth muscles. Nicorandil is a member of PCOs, with a special chemical structure. Recent investigations mention some novel effects and functions for this drug. Nicorandil reveals an anti-apoptosis property not only via a nitric oxide (NO)/cGMPdependent mechanism, but also through activating mitochondrial K-ATP channels. Nicorandil can also elevate cGMP levels in some tissues, without direct NO generation. Gastroprotective activity via opening of the K channels, free radical scavenging, prostaglandin E2 elevation, decreasing pepsin and acid secretion, and prevention of the detrimental rise in NO has been proposed for nicorandil. According to these protective mechanisms and the role of oxidative/nitrosative stress in the expression of IBD, we herein hypothesize that nicorandil and other PCOs with similar structure can be used in the management of IBD. This approach offers new hope for the successful treatment of IBD. Further investigations on animal models are needed, to place nicorandil and similar drugs alongside IBD therapy.

It is well known that inflammatory mechanisms play a crucial role in the pathogenesis of atherosclerosis and coronary artery disease. In recent years, allergic episodes have been shown to be associated with acute coronary syndromes. Mast cells release certain inflammatory mediators including histamine and neutral proteases during an allergic episode and these inflammatory mediators are implied to induce coronary artery spasm and/or atheromatous plaque erosion or rupture. As the inflammatory component of acute coronary syndromes is a potential therapeutic target, drugs that stabilize mast cell membrane and monoclonal antibodies that protect mast cell surface may be effective in preventing allergy associated acute coronary syndromes. In this review, we will mention the role of inflammation and allergy and antiinflammatory therapeutic modalities in acute coronary syndromes.

Metal-induced allergic contact dermatitis (ACD) is expressed in a wide range of cutaneous reactions following dermal and systemic exposure to products such as cosmetics and tattoos, detergents, jewellery and piercing, leather tanning, articular prostheses and dental implants. Apart from the well known significance of nickel in developing ACD, other metals such as aluminium, beryllium, chromium, cobalt, copper, gold, iridium, mercury, palladium, platinum, rhodium and titanium represented emerging causes of skin hypersensitivity. Despite the European Union directives that limit the total nickel content in jewellery alloys, the water soluble chromium (VI) in cement, and metals banned in cosmetics, the diffusion of metal-induced ACD remained quite high. On this basis, a review on the epidemiology of metal allergens, the types of exposure, the skin penetration, the immune response, and the protein interaction is motivated. Moreover, in vivo and in vitro tests for the identification and potency of skin-sensitizing metals are here reviewed in a risk assessment framework for the protection of consumer's health. Avenues for ACD prevention and therapy such as observance of maximum allowable metal levels, optimization of metallurgic characteristics, efficacy of chelating agents and personal protection are also discussed.

Peanuts are complex storage proteins with high contents and have been identified as one of the most allergenic foods. In this review, we summarize some of the latest findings and the potential importance of the Ara h 3 basic subunit, which has been overlooked as an allergen in early literature. Some recent studies indicate that Ara h 3 basic subunit may be as significant as or even a more important allergen than the acidic subunit. For example, one clinical study found a group of children with peanut allergy who were specifically sensitized to the basic subunit of Ara h 3. Although, proteomic analysis of total peanut storage proteins has revealed limited polymorphic profiles of major proteins in diverse peanut germplasm accessions, a study reported a peanut breeding line ‘GT-C9’ lacking several seed protein peptides, in which the missed major proteins were basic subunits of Ara h 3. This breeding line was shown to exhibit significantly lower levels of advanced glycation end (AGE) products and IgE binding by the sera of peanut allergic patients, which implies a role for the basic subunit of Ara h 3 in the allergenicity of peanuts. Further studies are needed to investigate the contribution of Ara h 3 basic subunits to peanut allergenicity.

The clinical expression of the most common allergic diseases reflects allergic inflammation and underlines that inflammation is the main target of anti-allergic therapies. Allergen specific immunotherapy (AIT) has a recognized impact on allergic inflammation, which persists after its discontinuation, and is the only therapy able to modify the natural history of allergic march. The traditional, subcutaneous route of administration is effective in altering the phenotype of allergenspecific T cells, switching from a Th2-type response, characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL- 32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy or tolerance of Th2, the latter related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual IT with high allergen doses proved to be similar compared to subcutaneous immunotherapy. Recent data obtained in biopsies clearly indicate that the pathophysiology of the oral mucosa, and in particular mucosal dendritic cells, plays a pivotal role in inducing tolerance to the administered allergen.

Adverse reactions to dietary proteins (DPs) can impose a significant impact on one's daily life and can even affect the ‘life style’ of an entire family. Adverse reactions to DPs may or may not be immune-mediated. The immunemediated adverse reaction to food is defined as food allergy (FA) which is roughly divided into IgE mediated or non-IgE mediated FA (NFA). As opposed to IgE mediated FA, NFA primarily affects the GI mucosa. In addition, there is far less of an understanding of NFA than IgE-mediated FA and its clinical relevance is likely under-estimated in most cases. This is partly due to delayed onset of symptoms and subsequent difficulty in making the clinical association between offending food and clinical symptoms. The lack of easily accessible diagnostic measures also contributes to the problem. The gut mucosal barrier is thought to have developed to execute an immensely difficult task; digestion and absorption of nutrients without provoking immune responses and cohabiting with commensal flora in a mutual beneficial relationship, while maintaining an immune defense against pathogenic microbes. The gut mucosal immune system accomplishes this task partly by establishing tolerance to macronutrients with potent immunogenecity. Immune tolerance to macronutrients (DPs) is maintained in part by active suppressive mechanisms involving antigen (Ag)-specific regulatory T (Treg) cells. This active immune tolerance state appears to be affected by various environmental factors such as change in commensal flora. In the first few years of life, humans gradually develop an intricate balance between tolerance and immune reactivity in the gut mucosa along with a tremendous expansion of gut associated lymphoid tissue (GALT). Not surprisingly, both IgE and non-IgE mediated food allergy (FA) is frequently seen during this period. The most common causative DPs for NFA are those contained in infant formulas (cow's milk and soy proteins). Unlike IgE mediated FA, NFA is rarely lifethreatening. However, NFA to DPs can cause significant morbidity in rapidly growing infants and young children. A better understanding of pathogenesis of NFA is crucial for timely management of NFA in this vulnerable population. This review discusses the gut mucosal immune system in the first few years of life including genetic/environmental factors affecting the development of mucosal immune system and pathogenesis of NFA in association with clinical/ laboratory findings.

Septic syndromes still remain a major but largely under-recognized healthcare problem worldwide accounting for thousands of deaths every year. Despite numerous clinical trials, therapies have failed to mitigate the devastating effects of these conditions. It is now agreed that the initial hypotheses for sepsis pathophysiology have been misconstrued. Sepsis deeply perturbs immune homeostasis by concomitantly inducing a strong inflammatory response and a major antiinflammatory process, acting as a negative feedback. Several lines of evidences indicate that this inhibitory response secondly may be deleterious in patients who survived initial resuscitation, as it may be directly responsible for worsening outcome by decreasing resistance to secondary nosocomial infections. In this context, while the majority of clinical and basic science conducted so far has focused on innate immune cell depressed functions (especially monocytes), the contribution of T lymphocyte anergy has been somewhat ignored. This review focuses on lymphocyte dysfunctions described so far in patients and on potential new therapeutic strategies aimed at restoring a functional lymphocytic response after sepsis.

In inflammatory bowel disease (IBD), such as UC and CD, the development of colorectal carcinoma can be initiated through chronic inflammation, depending on the duration and severity of the disease. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of colitis-associated cancer (CAC). For instance, TNF-α has been recently shown to promote tumor development in experimental colitis. Due to its role in the pathogenesis of IBD, TNF-α blockade has become one of the cornerstones of IBD therapy. Thus, anti-TNF-α strategies could also provide effective anti-tumor therapies. TGF-β has been shown to attenuate an anti-tumor immune-response through the induction of regulatory T cells in spontaneous and inflammation-associated cancer. However, IL-6 signaling promotes tumor growth in experimental CAC, and this signaling is inhibited by TGF-β. Members of the IL-12 family, such as IL-12, IL-23, and IL-27, have been implicated in pathogenesis of colitis and IL-23 seems to be involved in inflammation- associated carcinogenesis. However, a role for those cytokines in CAC remains to be shown. Whereas the above-mentioned cytokines promote tumor growth, others provide an anti-tumor effect. IL-10 deficient mice develop colitis and CAC a few weeks after birth. Besides its immunosuppressive properties, IL-10 also has anti-angiogenic and both tumor-promoting and -inhibiting properties, which could be responsible for these observations. Since most of the above mentioned cytokines are involved in both, inflammation and carcinogenesis, it is difficult to account their contribution to the individual steps during pathogenesis of CAC. However, as already shown in IBD, cytokines may also provide promising therapeutic targets in CAC.

Effects of compounds isolated from medicinal plants in Korea on prostaglandin E2 (PGE2) production in rat peritoneal macrophages were examined, and mechanism of action of the active constituents was analyzed. The active constituents were as follows; tectorigenin and tectoridin isolated from the rhizomes of Belamcanda chinensis, platycodin D isolated from the roots of Platycodon grandiflorum, imperatorin isolated from the roots of Angelica dahurica, and hyperin isolated from the roots of Acanthopanax chiisanensis. These compounds inhibit the induction of cyclooxygenase-2 (COX- 2), thus inhibiting PGE2 production. The chemically synthesized chalcone derivative, 2'-hydroxy-4'-methoxychalcone, also inhibits PGE2 production by suppressing COX-2 induction. In contrast, taiwanin C isolated from the roots of Acanthopanax chiisanensis inhibited PGE2 production by direct inhibition of COX-1 and COX-2.

Autoimmunity results from the dysregulation of the immune system leading to tissue damage. Th1 and Th17 cells are known to be cellular mediators of inflammation in autoimmune diseases. The specific cytokine milieu within the site of inflammation or within secondary lymphatic tissues is important during the priming and effector phases of T cell response. In this review, we will address the nature of the inflammatory response in the context of autoimmune disease, specifically we will discuss the role of dendritic cells following stimulation of their innate pathogen recognition receptors in directing the development of T cell responses. We will focus on how dendritic cell subsets change the balance between major players in autoimmunity, namely Th1, Th17 and regulatory T cells. Th17 cells, once thought to only act as pathogenic effectors through production of IL-17, have been shown to have regulatory properties as well with co-production of the anti-inflammatory cytokine IL-10 by a subset now referred to as regulatory Th17 cells. IL-17 is important in the induction of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and inflammatory bowel disease (IBD). Study of the inflammatory process following encounter with agents that stimulate the innate immune responses such as adjuvants opens a new horizon for the discovery of therapeutic agents including those derived from microorganisms. Microbial products such as adjuvants that function as TLR ligands may stimulate the immune system by interacting with Toll-like receptors (TLR) on antigen-presenting cells. Microbial agents such as Bacille Calmette-Guerin (BCG) or Freund's adjuvant (CFA) that induce a Th17 response are protective in models of autoimmune diseases particularly EAE and type 1 diabetes (T1D). The induction of innate immunity by these microbial products alters the balance in the cytokine microenvironment and may be responsible for modulation of the inflammation and protection from autoimmunity.