Inflammation & Allergy-Drug Targets (v.12, #1)

Cutting Edge: Chemoprevention of Colorectal Neoplasia in Inflammatory Bowel Disease by Giovanni C. Actis, Sonia Tarallo, Floriano Rosina (1-7).
Colitis-associated cancer represents a long-standing problem, with two new factors adding to its importance: the diffusion of inflammatory bowel disease in developing countries, and the increased availability of effective drugs that control ulcerative colitis delaying or abrogating the need for a curative colectomy. The consolidated evidence that inflammation is the unique variable that factors in colitic cancer development has conferred impetus to the search and release of anti-inflammatory/immune suppressive molecules to pursue the goal of cancer chemoprevention. Cutting-edge research has provided breakthrough insights into the mechanism of the chemopreventive actions of mesalamines, thiopurines, and probiotics, and we expand on these topics. Despite these advancements, bedside evidence is still mixed and calls for further scrutiny. Nowadays, the clinician must continue to rely on classic preventive measures such as surveillance colonoscopy, and the early and aggressive use of drugs that permit to keep the degree of mucosal inflammation to a minimum.

Background: Understanding the etiopathogenesis of chronic spontaneous urticaria (CSU) remains a challenge. The clinical and laboratory characteristics relating to its histocompatibility profile and autoimmunity are constant research topics. Objectives: To analyze the clinical and laboratory characteristics of patients with CSU by means of a cross-sectional study, focusing on the histocompatibility profile, presence of antinuclear antibodies (ANA) and presence of antithyroperoxidase antibodies (anti-TPO). Materials & Methods: Sixty-seven adults with CSU were analyzed. The autologous serum skin test (ASST), ANA and anti-TPO were performed in all cases and MHC classes I and II (loci A, B and DR) were evaluated in 49 patients. Results: The factors that worsened urticaria included use of non-steroid anti-inflammatory drugs, emotional stress and physical stimuli, reported by 27%, 16% and 15% of these patients, respectively. The ASST test was positive in 49 patients (73%) and anti-TPO and ANA were present in 15 (22.4%) and 7 (10.5%), respectively. The OR (with 95% CI) for the association between ANA and anti-TPO was 5.94 (1.16-30.42), and thus statistically significant. There was a favorable association (with statistical significance) between HLA B*50 and patients with CSU, with OR (95% CI) of 2.96 (1.17- 7.48). Conclusion: A significant favorable association was found between these patients and HLA B*50, and between the presence of anti-TPO and ANA. The greater prevalence of HLA B*50 in these patients and the association between ANA and anti-TPO reinforce the possibility that an immunogenic mechanism may be the triggering factor for CSU.

Immunotherapy in Allergies: An Update by Zamir Calamita, Simone Bernardino Potthast (12-18).
The allergen specific immunotherapy is the administration, in IgE-mediated allergic patients, of a specific allergen in a gradually increased number to provide protection against allergic symptoms and inflammatory reaction. The current immunotherapeutic approaches occur by modulating the release of inflammatory mediators involved in allergic reaction and consequently the inhibition of allergic inflammatory process. Since 1997 several World Associations of Allergy, Asthma and Immunology, have reviewed this issue, seeking to establish standards for its use. Also many publications about the immunotherapy's efficacy, as well as, several guidelines on the use of immunotherapy in the treatment of allergic are available. This article will focus on the most current evidence about the immunotherapy in allergies regarding its mechanism of action, effectiveness and practical considerations.

Allopurinol Hypersensitivity Reactions: Desensitization Strategies and New Therapeutic Alternative Molecules by Gianfranco Calogiuri, Eustachio Nettis, Elisabetta Di Leo, Caterina Foti, Antonio Ferrannini, Lavjay Butani (19-28).
Allopurinol, an analog of hypoxanthine has been worldwide used for the treatment of hyperuricemia and gout for over 40 years. Unfortunately some patients assuming this medication have developed hypersensitivity reactions ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome or Steven-Johnson syndrome and lethal toxic epidermal necrolysis. Various strategies of slow desensitization have been elaborated to reintroduce allopurinol in a part of these patients, mainly patients affected by mild skin reactions as fixed drug eruption or exanthema. However, several new uricosuric therapies have been recently introduced. Actually drugs as recombinant urate oxidase and febuxostat are under post-marketing surveillance to control potential adverse effects related to their immunogenicity even.

The Role of Exosomes in Infectious Diseases by Hamideh Mahmoodzadeh Hosseini, Abbas Ali Imani Fooladi, Mohammad Reza Nourani, Faezeh Ghanezadeh (29-37).
An exosome is a nano vesicle that buds from the endosomal compartment; it is produced and released by all kinds of mammalian cells. This vesicle contains a variety of proteins, lipids, mRNAs and miRNAs. These components are specific to the origin of the exosomes and contribute to cell-cell communications. Recently, it has been reported that a few single cell eukaryotic pathogens such as Cryptoccoccus neoformance and Leishmania major and donovanican secrete an exosome and influence the host immune system. In addition, it has been observed that cells infected by intracellular pathogens are capable of secreting an exosome which is involved in the fate of the infection. Furthermore, retroviruses recruit the host`s endosomal compartments in order to generate viral vesicles which are similar to the exosome. Most of the exosomes involved in infectious biology can either spread or limit an infection based on the type of pathogen and its target cells. Hence, an exosome may be an appropriate candidate for a vaccine therapy in prophylaxis and treatment.

Update on the Principles and Novel Local and Systemic Therapies for the Treatment of Non-Infectious Uveitis by Roberto Gallego-Pinazo, Rosa Dolz-Marco, Sebastian Martinez-Castillo, J. Fernando Arevalo, Manuel Diaz-Llopis (38-45).
Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non-infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to play the role of corticosteroid-sparing agents. These can be organized in four other steps: cyclosporine and methotrexate in a second one; azathioprine, mycophenolate and tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a last one with cyclophosphamide and chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non-infectious posterior uveitis.

Pathophysiological Bases of Eosinophilic Esophagitis Therapy by Ricardo Moreno-Borque, Javier P. Gisbert, Cecilio Santander (46-53).
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of unknown etiology, presenting a dense mucosal infiltration of eosinophils that is not reversible with proton pump inhibitor therapy. Endoscopy has reported EoE commonly polymorphous disease with subtle mucosal changes, accompanied by variations in the caliber of the esophagus. The suggestion of EoE as an allergic disease is still short of evidence and recently, it has only been confirmed that the esophagus mucosal layer infiltrated by eosinophils may determine an association with allergy after exposure to allergens. A comprehensive review of symptoms, risk factors, diagnoses and mechanisms involved in the pathogenesis of EoE was carried out, with an analysis of the different treatment options available for this disease firmly maximizing in incidence and prevalence. The management of EoE is multidisciplinary and can involve gastroenterologists, pathologists, allergists and dietitians, particularly in pediatric patients, because dietary food restrictions appear to be more beneficial in children versus adults. EoE can successfully be treated with topical corticosteroids, which eliminate the clinical manifestations and histological lesions in most cases. Prolonged treatment is advised for EoE because it recurs frequently, particularly on discontinuation of therapy. Experimental treatments using immunotherapy are being investigated, but their safety and efficacy are yet to be defined.

Severe or refractory bronchial asthma represents 5-10% of the asthmatic population that responds poorly to high doses of inhaled corticosteroids. Biopharmaceutical approaches have identified new therapies that target key cells and mediators, such as Th2-cells, cytokines, and chemokines. However, some of the clinical trials with these biologics in patients with asthma have been unsuccessful, thus some of these studies had to be discontinued. This article will review current therapeutic strategies of biological immune response modifiers in decreasing pathological immune responses. Therapies using cytokine inhibitors currently provide a way to elucidate the role of individual cytokines in the pathogenesis of human diseases and may yield new approaches to identifying asthma phenotypes.

Peyronie's Disease (PD) is a connective tissue disorder involving the growth of fibrous plaques in penile corpora cavernosa (tunica albuginea). The conservative treatment is indicated in the development stage of PD for at least one year after diagnosis and in case of penile pain. This study was conducted to demonstrate the possible effectiveness of the new substances of Peironimev-plus®. Sixty four patients (age: 29-65 years, mean: 52.57 ± 9.06) diagnosed with PD were enrolled in a medical treatment. All patients underwent the following diagnostic tests: penile ultrasound, photographic documentation of penile curvature, IIEF questionnaire (erectile function score), pain evaluation with Visual Analogue pain Scale (VAS). The patients were divided into two treatment groups with different combinations of drugs: A = Peironimev-plus/oral/one tablet-daily + Verapamil injection (peri-lesional) 10 mg/every two weeks + Verapamil iontophoresis/5 mg/three times a week - for 6 months; B = Verapamil injection (peri-lesional) 10 mg/every two weeks + Verapamil iontophoresis/5 mg/three times a week - for 6 months. Intergroup analysis revealed statistically significant differences: in group A the effective plaque size reduction was -30.8% while in the group B the reduction was -18.0% (p=0.000). In group A the improvement of curvature occurred in 85.1% of the cases while in group B this occurred only in 53.5% (p=0.024), moreover the mean curvature decrease was respectively - 8.7° and - 4.6° (p=0.002). IIEF score was significantly improved in group A patients with erectile dysfunction (p=0.02). Our results suggest that Peironimev-plus is an effective drug in treating PD and it may help to prevent the progression of PD.

Inflammation or vascular occlusion by parasitized red blood cell contributes to the pathogenesis of cerebral malaria. The current study aimed to characterize the role of major pro-oxidant factor methemoglobin present in the malaria culture supernatant contributing in inflammation during malaria. Heme and heme polymer stimulate macrophage to secrete large amount of reactive oxygen species into the external micro-environment. The addition of methemoglobin along with heme or heme polymer amplifies production of ROS from macrophages several folds. Methemoglobin mediated stimulatory effect is not due to release of iron, enhanced production of H2O2 or mutual interaction of reaction components. Spectroscopic studies show that methemoglobin accepts heme as a substrate and oxidizes it through a single electron transfer mechanism. Heme oxidation product is a heme polymer with similar chemical and structural properties to synthetic β-hematin. Phenyl N-t-butylnitrone inhibits heme polymerization (IC50=30 nM) and indicates the absolute necessity of heme oxidation and heme free radical generation for heme polymerization. Methemoglobin produced heme polymer is a potent pro-inflammatory factor to release ROS into external microenvironment. Interestingly, methemoglobin not only produces pro-inflammatory heme polymer, but it also amplifies the potential of heme or preformed heme polymer (haemozoin or β-hematin) to produce several folds high ROS production from macrophages. This study illustrates the pro-inflammatory effect of methemoglobin, the underlying novel mechanism by which this occurs and a possible clinical intervention. Based on the results, we recommend methemoglobin directed peroxidase inhibitors as an adjuvant therapy during malaria.