Inflammation & Allergy-Drug Targets (v.11, #4)

Aims: This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and - challenged peri-bronchial vascular inflammation and remodeling in mice. Methods and Results: After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)- pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases-9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intraperitoneal OVA on day 1 and day 8, challenged with OVA nebulization and treated with KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NOmetabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar regions. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1. Conclusions: Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.

Antagonizing IL-6 in Ankylosing Spondylitis: A Short Review by Sakthiswary Rajalingham (262-265).
Ankylosing spondylitis (AS) is a chronic inflammatory disorder with predilection for the axial skeleton, leading to progressive restricted mobility and deformity of the spine. The fundamental mechanism involves autoimmunity orchestrated by T cells. Similar to other rheumatic diseases, the complex interplay of cytokines such as tumour necrosis factor alpha, interleukin-6 (IL 6) and interleukin-10 (IL 10) has been implicated in the pathogenesis of the disease. Despite extensive research over the past decades, the treatment options for AS, are limited. Non steroidal antiinflammatory drugs are the first line of therapy, whereas anti TNF drugs are administered for refractory cases which fail to respond to the treatment. There have been conflicting views on the correlation of IL 6 with disease activity in AS. As such, the debate on the role of anti IL6 in AS is still ongoing. Anti IL 6 such as tocilizumab and siltuximab have proven efficacy based on the large randomized controlled trials. The Food and Drug Administration (FDA) has approved these drugs for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis. Researchers have adventurously experimented anti IL 6 therapy in AS but the conclusions made were not consolidated into international guidelines or consensus statement for clinical practice. In the present review, we explore the role of anti IL6 in the treatment of AS based on the cumulative evidence over recent years.

Systemic sclerosis is an autoimmune connective tissue disorder characterized by fibrosis of the skin and visceral organs. Interstitial lung disease (ILD) is a major complication of this disease and along with pulmonary arterial hypertension is the leading cause of mortality in scleroderma patients. The pathogenesis of pulmonary fibrosis is characterized by epithelial cell injury, activation of the coagulation pathway and inflammation, which create a profibrogenic environment in the lung in the setting of autoimmunity. The current standard of treatment for ILD in systemic sclerosis is cyclophosphamide. In view of the modest benefits in pulmonary function seen with cyclophosphamide in two recent trials and its significant toxicity, the search for alternative treatments is ongoing. With the advances in our understanding of the pathogenic mechanisms of pulmonary fibrosis, many promising therapeutic agents have come into view, but their efficacy needs to be evaluated before they can be recommended clinically. This review discusses the pathogenesis of pulmonary fibrosis with a focus on the potential target pathways, the current treatment options and recent advances in the treatment of ILD in systemic sclerosis.

Transglutaminases (TGs, E.C. are 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. To date, at least eight different human TGs have been identified. 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 patho-genetic mechanisms responsible for several human diseases. In particular, TG2, a member of the TG enzyme family, has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD), one of the most common food intolerances described in the western population. The main food agent that provokes the strong and diffuse clinical symptoms has been known for several years to be gliadin, a protein present in a very large number of human foods derived from vegetables. The aim of this review is to summarize the most recent findings concerning the relationships between the biochemical properties of the transglutaminase activity and the basic molecular mechanisms responsible for CD. In addition, we present some clinical associations of CD with other human diseases, with particular reference to neuropsychiatric disorders. Possible molecular links between biochemical activities of transglutaminase enzymes, CD and neuropsychiatric disorders are discussed.

The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and 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 of Th2 or to tolerance, the latter being 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 AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen.

Asthma is increasingly being recognised as involving not only allergic inflammatory mechanisms but also a variety of other cell types and cytokines. While the role of interferon-γ(IFN-γ) in asthma remains controversial, it has been proposed to contribute to the pathogenesis of both chronic stable asthma and acute severe asthma. We have shown that in a model of chronic allergic asthma in mice, airway hyper-responsiveness (AHR) is independent of various Th2 cytokines and their signalling pathways, but is dependent on IFN-γ. In a model of an allergen-induced acute exacerbation of chronic asthma, we have demonstrated that activation of pulmonary macrophages may play a critical role in driving the inflammatory response. Furthermore, we have demonstrated that IFN-γstimulation of macrophages can lead to steroidresistant airway inflammation and AHR via the production of interleukin-27. These findings strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves both Th2 and Th1 cytokines, as well as interaction between the allergic response and the innate host defence system. Targeting the effects of IFN-γon pulmonary macrophages may be particularly relevant to the treatment of steroid-resistant acute exacerbations of asthma.

Leptin is an adipokine whose proinflammatory properties contribute to the pathogenesis of several autoimmune diseases but also to the development and progression of inflammation in several non-autoimmune inflammatory conditions of the kidney, liver, lung, endometrium, blood vessels and endothelia. Here we review the influences of leptin in those conditions and the pertinent experimental work that has defined some mechanisms of action and/or suggested a therapeutic potential for leptin-based modulation of inflammation in non-autoimmune conditions.

Kidney apoptosis and fibrosis are an inevitable outcome of progressive chronic kidney diseases where congenital obstructive nephropathy is the primary cause of the end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro-inflammatory cytokines, NF-κB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidence reports that angiotensin II (a pro-inflammatory hormone) increases the mitochondrial oxidative stress regulating apoptosis induction. This review summarizes our understanding about possible mechanisms that contribute to apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of antiinflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies.

Interleukin-21 in Immune and Allergic Diseases by Massimiliano Sarra (313-319).
Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses. IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R), and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells. IL-21 controls also the activity of non-immune cells, such as epithelial cells and stromal cells. The demonstration that IL-21 is involved in the immune responses occurring in chronic inflammatory and allergic diseases suggests that either disrupting or enhancing IL-21 signalling may be useful in specific clinical settings.

Background: Food allergies are important etiologic factors in atopic dermatitis. CD19 is a B-cell-specific cellsurface molecule, with a critical role in B-cell activation. Recently, B cells showed independent two subpopulations as CD19hi and CD19low. The allergen-specific responses of the CD19high and CD19low B-cell subpopulations were investigated in patients with non-IgE-mediated food allergy. Methods: Five milk-allergic subjects and eight milk-tolerant subjects were selected by a double-blind placebo-controlled food challenge. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with casein or ovalbumin and stained with monoclonal antibodies to distinguish the B-cell subsets. Results: After allergen stimulation, CD19high B cells increased in the number and the fraction in PBMCs in the milktolerant group, whereas those remained unchanged in the milk-allergic group. These responses were constant, regardless of the kind of food allergen (milk or egg). The resulting CD19high/CD19low B-cell ratio increased markedly in the milktolerant group after allergen stimulation, but was unchanged in the milk-allergic group. IL-10, IL-17, IL-32 and TGF-β- producing regulatory B cells and Foxp3-expressing regulatory B cells were identified predominantly on CD19 low and CD5(+) B cells. Conclusions: The response of the CD19high B-cell subpopulation to allergen stimulation is decisive for immune tolerance of non-IgE-mediated food allergy in atopic dermatitis. CD19 high and CD5(+) B cells dominantly produce cytokines and express Foxp3. Especially, IL-17 and IL-32 expressing B cells (Br17 & Br32) are present. The exact immunological role of CD19 and cytokines including IL-17 and IL-32 around B cells in immune tolerance requires further investigation.

Treatment of Guillain-Barre Syndrome: A Review by Yusuf A. Rajabally (330-334).
Guillain-Barre syndrome is a frequently post-infectious, autoimmune acute inflammatory polyradiculoneuropathy affecting all age groups. It typically results in rapid-onset weakness symmetrically affecting proximal and distal muscles. Cranial muscles are not infrequently affected and respiratory muscle weakness requiring mechanical ventilation occurs in 25% of cases. The incidence is around 1-2 per 100,000/year. Various clinical, electrophysiological and immunological subtypes are described. Plasma exchanges (PE) and intravenous immunoglobulins (IVIg) represent the main treatment options. PE were shown to be effective on rate of recovery in randomized trials. Subsequently further trials have demonstrated the equivalence of IVIg. IVIg are frequently the preferred option for practical reasons. Treatment can result in reversible clinical fluctuations which need to be readily recognized. Although number of PE appears to be optimally of 4, except in mildly affected patients where only 2 may suffice, the dosage of IVIg conventionally administered (2 g/kg) may be sub-optimal in some patients. This may relate to a relationship between IVIg pharmacokinetics and clinical outcome. Studies are under way to evaluate the usefulness of a second IVIg course in severely-affected GBS patients. There is no evidence for use of corticosteroids in GBS. Both IVIg and PE are costly and despite their use and established effectiveness, there is still a need for new treatments to lessen disability. Further research is warranted in optimizing currently available therapies as well as finding others to effectively improve the management of this potentially devastating condition.