Inflammation & Allergy-Drug Targets (v.7, #4)

Dendritic cells (DC) exert important functions both in the induction of protective T cell immunity, as well as in the induction of tolerance. The latter is essential in protection against the development of allergy. Exposure to pathogenassociated molecular patterns (PAMPs), that signal through different Toll-like receptor (TLR)s, modulates production by DC of several Interleukin(IL)-12 family members: IL-12p70, IL-23, IL-27 and IL-35. The production of those cytokines in turn differentially influences both T cell differentiation and effector T cell activation. We focus in this review on myeloid and plasmacytoid DC and their role in development of allergic diseases. In particular, we focus on differences in DC activation between healthy and allergic individuals. Furthermore we discuss the activation of DC by TLR-ligands and their differential cytokine induction. Finally, we discuss preclinical studies and potentially therapeutic options using TLRligands for allergic diseases.

Regulatory T Cells as Targets for Immunotherapy of Autoimmunity and Inflammation by Wiebke Hansen, Astrid Westendorf, Jan Buer (217-223).
Regulatory T (Treg) cells are emerging as key players in the regulation of different immune responses, thereby representing potential candidates for therapeutic interventions in a broad variety of immunological disorders. While the reduction or loss in function would be of benefit during the treatment of cancer, induction and/or expansion of Treg cell function might be helpful to interfere with unwanted immune responses in transplantation medicine, during autoimmunity, allergy and inflammation. However, a better understanding of Treg cell biology is a prerequisite to specifically modulate its function during immune responses in vivo. In the present review we will discuss current concepts on different cell types, components and some novel surface receptors expressed by Treg cells, namely Neuropilin-1, CD83 and G proteincoupled receptor 83 which might represent promising targets for the modulation of Treg cell function in human disease.

Airway remodeling is a characteristic feature of allergic asthma that is now thought to contribute to airway dysfunction and, ultimately, to clinical symptoms. A prevalent hypothesis holds that eosinophil-derived transforming growth factor-and#946; (TGF-and#946;) is a predominant underlying mechanism driving the development of remodeling and thus, represent promising targets for therapeutic intervention. This notion is supported by in vivo evidence from loss of function experiments conducted in animal models employing the surrogate allergen ovalbumin (OVA), and by indirect evidence from studies in human asthmatics. However, it is important to note that various studies in OVA systems have reported disconnects between eosinophils, TGF-and#946; and allergic remodeling. Moreover, recent investigations in a mouse model induced by respiratory exposure to a house dust mite extract have shown that remodeling can develop independently of TGF-and#946;. These findings challenge the above hypothesis and suggest that the mechanisms governing remodeling may be context specific. In addition to TGF-and#946; and eosinophils, several other factors have been implicated in the development of airway remodeling. Among these, interleukin (IL)-13 may be of particular importance given its role in type-2 immunity and in the tissue repair/fibrotic response. This review will appraise the evidence pertaining to the roles of TGF-and#946;, eosinophils and IL-13 in allergic remodeling, and will suggest that identifying robust targets for therapeutic intervention might benefit from a reconsideration of our approach to understanding remodeling.

Regulatory T Cells and Allergic Disease by Kayhan Nouri-Aria, Stephen Durham (237-252).
Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect about 15and#x25; of the population in countries such as the UK or USA. Regulatory T cells (TRegs) have been shown to be critical in the maintenance of immune responses and T cell homeostasis. For example, depletion of CD4+CD25+ TRegs from mice resulted in the development of multiorgan autoimmune diseases. So-called and#x2018;naturaland#x2019; CD4+CD25+ TRegs and/or IL-10-producing Tr-1 cells are capable of suppressing Th2 responses to allergens in health, whereas such inhibition is attenuated in allergic conditions. In this context, both cell-cell contact-dependent (either through membrane bound TGF-and#946; or via suppressive molecules such as CLTA-4) and soluble cytokine- (TGF-and#946; and IL-10) dependent mechanisms have been shown to contribute to the function of TRegs. Moreover, adoptive transfer of CD4+CD25+ TRegs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10 and TGF-and#946; producing Tr-1 cells as well as Foxp3 expressing IL-10 T cells, with resulting suppression of the Th2 cytokine milieu. Activation and expansion of antigen-specific CD4+CD25+ TRegs in vivo using adjuvants or pharmacological agents such as low dose steroids or vitamin D3 could represent novel approaches to induce antigen-specific tolerance in human diseases including allergic asthma, autoimmune disease and the rejection of transplanted organs.

Tuning Immune Suppression in Systemic Autoimmunity with Self-Derived Peptides by Ram Singh, Bevra Hahn, Antonio Cava (253-259).
A central pathologic mechanism in systemic autoimmune diseases with chronic inflammation such as systemic lupus erythematosus (SLE) is the aberrant production of antibodies against self-components produced by abnormal B cells with the help of hyperactive CD4 T cells. One goal for better control of the disease is the limitation of the number of abnormal and hyperactive cells, to prevent and/or attenuate the damaging effects of the pathogenic antibodies on target tissues. Recently, a role of regulatory T cells in the suppression of autoimmune reactivity in diseases including SLE has been recognized. CD4 CD25 , regulatory T cells (Tregs) and CD8 inhibitory T (Ti) cells have been found numerically decreased and/or functionally impaired in some patients with active systemic lupus erythematosus. Recent experimental work and preclinical studies have also provided proof-of-concept for the possibility of induction of self-tolerance through the modulation of regulatory/suppressor T cells using self antigen-derived peptides that could promote suppression of the production of pathogenic antibodies. This review explores the mechanisms elicited by the administration of self antigenderived peptides on the induction of suppression of autoimmune responses, and how this information might lead to future development of new strategies for better management of systemic autoimmune conditions.

Pulmonary Arterial Hypertension: Need to Treat by Dimosthenis Lykouras, Fotis Sampsonas, Alex Kaparianos, Georgios Efremidis, Kiriakos Karkoulias, George Tsoukalas, Kostas Spiropoulos (260-269).
Pulmonary Arterial Hypertension (PAH) is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures. It is characterized by increased pulmonary vascular resistance due to increased vascular tone and structural remodeling of pulmonary vessels. PAH is a quite rare condition, thus considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread. In order to reach a diagnosis the use of echocardiography, right-heart catheterization and the six-minute walk test is essential. As far as therapy is concerned, the patient should be supported by oxygen, diuretics, anticoagulants, digoxin and suggest life-style changes. After diagnosing the condition ca-blockers should be administered to those who respond positively in acute vasodilation test. Other agents used, target the endothelin pathway (ET-1 blockers such as bosentan), the NO pathway (sildenafil, inhaled NO, L-arginine) and the prostacyclin pathway (prostacyclin analogues). In some cases surgical treatment is essential (atrial septestomy, pulmonary endarterectomy, lung and heart transplantation). Finally, future therapies include administration of VIP and SSRIs. The goals of evaluating pulmonary hypertension are detection, definition of severity and the nature of the hemodynamic lesion and its consequences, diagnosis of causal or associated conditions, and determination of optimal therapy.

Specific immunotherapy is a clinically effective causative treatment for allergic conditions. However, the reagents used for immunotherapy are crude extracts, prepared from natural sources, and as such may cause potential lifethreatening anaphylactic side effects. Our increasing knowledge of mechanisms that lead to allergy and of the mechanisms of successful immunotherapy have introduced new ideas for the treatment of allergic diseases. Techniques of biochemistry and molecular biology have made it feasible to design novel therapeutic approaches for improved and safer forms of allergen-specific immunotherapy. The purpose of this review is to examine different approaches in designing novel allergen formulations for specific immunotherapy. These include chemically modified forms of allergens, genetically modified allergens (hypoallergens), hybrid allergens and allergens bearing immunostimulatory molecules, or adjuvants, which foster Th 1 immune responses. There is great interest in newly designed allergens and their derivatives to improve the efficacy and safety of allergen immunotherapy. A better understanding of immunological mechanisms and further clinical trials utilizing new allergen formulations are needed.

Macrolide Therapy Targets a Specific Phenotype in Respiratory Medicine: From Clinical Experience to Basic Science and Back by Bart Vanaudenaerde, Robin Vos, Isabelle Meyts, Stephanie De Vleeschauwer, Stijn Verleden, Anna Widyastuti-Willems, Wim Wuyts, Dirk Van Raemdonck, Peter Hoet, Lieven Dupont, Benoit Nemery, Geert Verleden (279-287).
For centuries a quest has been going on for the and#x201C;holy grailand#x201D; in respiratory medicine: a treatment for numerous devastating chronic lung disorders. Yet, it is only a decade ago that pharmacological interference with the activation of the innate immune system by a macrolide antibiotic silently moved into everyday clinical practice. Macrolides, with their unique molecular structure built around a lactone ring, are now known to target harmful exaggerated innate immune responses. However, not all chronic lung conditions benefit from macrolide therapy and interestingly, neither do all patients with an apparently identical chronic lung disease. A subgroup of and#x2018;respondersand#x2019; seems to display a single specific phenotype that can be recognized in the various lung conditions and that seems to be related to inflammatory responses with a predominant innate immune system component. Recently we have contributed to the introduction of macrolide therapy in lung transplantation medicine. Also we attempted to analyse this phenotype by describing its clinical, immunological, histological and radiological characteristics. The aim of this manuscript is to review the use of macrolides in the respiratory field and to apply the macrolide-responsive phenotype beyond the setting of lung transplantation and other conditions in which macrolides have been successful. The description of this and#x201C;universaland#x201D; macrolide-responsive phenotype can both help rationalize macrolide therapy in respiratory disorders, in which its benefit is already well-known, as well as promote the use of this treatment in respiratory conditions of unknown etiology but with a and#x201C;macrolide responsive phenotypeand#x201D;.

The prevalence of allergy and asthma has been increasing steadily in the developed world. Despite the growing health problems associated with these conditions few new therapeutic options are becoming available. Relatively recent developments have identified a role for proteases in promoting allergic sensitisation and allergic airway inflammation. It is also known that most major allergens have associated protease activity that is closely related to their efficacy to induce sensitization and inflammation. Here we review the evidence for the significance of protease activity in allergic airway disease and offer suggestions as to where the field could progress.