Gilda Varricchi

Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs

Purpose of reviewHuman eosinophils were first identified and named by Paul Ehrlich in 1879 on the basis of the cells granular uptake of eosin. Although eosinophils represent approximately 1% of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophils and their mediators are critical effectors to asthma and eosinophilic granulomatosis with polyangiitis (EGPA). Eosinophils are equipped with a large number of cell-surface receptors and produce specific cytokines and chemokines. Recent findingsEosinophils are the major source of interleukin-5 and highly express the interleukin-5R&agr; on their surface. Clinical trials evaluating monoclonal antibodies to interleukin-5 (mepolizumab and reslizumab) and its receptor interleukin-5R&agr; (benralizumab) have been or are underway in patients with eosinophilic asthma, EGPA and chronic obstructive pulmonary disease (COPD). Overall, targeting interleukin-5/interleukin-5R&agr; is associated with a marked decrease in blood and sputum eosinophilia, the number of exacerbations and improvement of some clinical parameters in adult patients with severe eosinophilic asthma. Pilot studies suggest that mepolizumab might be a glucocorticoid-sparing treatment in patients with EGPA. A preliminary study found that benralizumab did not reduce the exacerbations and did modify lung function in patients with eosinophilic COPD. SummaryThe review examines recent advances in the biology of eosinophils and how targeting the interleukin-5 pathway might offer benefit to some patients with severe asthma, EGPA, and COPD. Interleukin-5/interleukin-5R&agr;-targeted treatments offer promises to patients with eosinophilic respiratory disorders.

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis

Angiogenesis, namely, the growth of new blood vessels from pre-existing ones, is an essential process of embryonic development and post-natal growth. In adult life, it may occur in physiological conditions (menstrual cycle and wound healing), during inflammatory disorders (autoimmune diseases and allergic disorders) and in tumor growth. The angiogenic process requires a tightly regulated interaction among different cell types (e.g. endothelial cells and pericytes), the extracellular matrix, several specific growth factors (e.g. VEGFs, Angiopoietins), cytokines and chemokines. Lymphangiogenesis, namely, the growth of new lymphatic vessels, is an important process in tumor development, in the formation of metastasis and in several inflammatory and metabolic disorders. In addition to tumors, several effector cells of inflammation (mast cells, macrophages, basophils, eosinophils, neutrophils, etc.) are important sources of a wide spectrum of angiogenic and lymphangiogenic factors. Human mast cells produce a large array of angiogenic and lymphangiogenic molecules. Primary human mast cells and two mast cell lines constitutively express several isoforms of angiogenic (VEGF-A and VEGF-B) and the two lymphangiogenic factors (VEGF-C and VEGF-D). In addition, human mast cells express the VEGF receptor 1 (VEGFR-1) and 2 (VEGFR-2), the co-receptors neuropilin-1 (NRP1) and -2 (NRP2) and the Tie1 and Tie2 receptors. Immunologically activated human basophils selectively produce VEGF-A and -B, but not VEGF-C and -D. They also release Angiopoietin1 that activates Tie2 on human mast cells. Collectively, these findings indicate that human mast cells and basophils might participate in the complex network involving inflammatory and tumor angiogenesis and lymphangiogenesis.

Are Mast Cells MASTers in Cancer

Prolonged low-grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content, and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of pro-tumorigenic (e.g., angiogenic and lymphangiogenic factors) and antitumorigenic molecules (e.g., TNF-α and IL-9), depending on the milieu. In certain neoplasias (e.g., gastric, thyroid and Hodgkin’s lymphoma) mast cells play a pro-tumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicates that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary, or innocent bystanders in human cancers.

Omalizumab in patients with eosinophilic granulomatosis with polyangiitis: a 36-month follow-up study

Abstract Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterized by asthma and blood eosinophilia, with the lung being the organ most frequently affected. Oral glucocorticoids and/or immunosuppressive drugs are the mainstay therapy of EGPA. Occasional reports suggest that EGPA patients can be treated with omalizumab in addition to conventional therapy to achieve asthma control. To investigate the long-term effects of omalizumab in patients with EGPA and asthma (2 females, 3 males, age 41–64 years), we carried out a 36-month follow-up observational study. At the time of enrollment, the patients were on maintenance therapy and had moderate to severe allergic asthma, eosinophilia and rhinosinusitis. Mononeuropathy/polyneuropathy and/or histological evidence of tissue eosinophilic infiltration were also present. Methods: Patients were treated with omalizumab (300–600 mg s.c. every 2–4 weeks) as add-on therapy to prednisone, inhaled steroids and bronchodilators. During omalizumab treatment, spirometry, the asthma control test (ACT) score and eosinophilia were evaluated, and prednisone dosage was recorded. Results: During the 36 months of omalizumab treatment asthma progressively improved as indicated by spirometry and the ACT score. Eosinophilia progressively decreased. The oral prednisone dose was reduced or withdrawn during treatment. No adverse events were recorded. Conclusions: In patients with EGPA and moderate to severe allergic asthma, omalizumab can be beneficial and safe. It enables corticosteroid tapering while decreasing eosinophilia and improving asthma symptoms over 36 months.

Basophils: historical reflections and perspectives.

Basophils were discovered by Paul Ehrlich in 1879 and account for less than 1% of blood leukocytes, which suggests a tightly controlled regulation of basopoiesis. The conservation of basophils in a wide spectrum of the animal kingdom suggests a non-redundant role in innate and adaptive immunity. In the early 1990s, it was demonstrated that murine and human basophils synthesize interleukin (IL)-4 and IL-13, thereby suggesting that these cells are important for Th2 polarization and IgE synthesis. Human basophils also synthesize IL-3, VEGFs and other pro-angiogenic molecules. Recently, various groups have introduced the use of basophil-depleting antibodies or have developed transgenic mice that constitutively lack basophils by more than 90%. These models have highlighted previously unrecognized roles of basophils, distinct from those played by mast cells, in innate and adaptive immunity. Although the physiologic role of basophils remains unknown, there is now compelling evidence that basophils, despite their small numbers in peripheral blood and inflamed tissues, are critically involved in a wide spectrum of immunologic disorders (allergic, autoimmune and infectious diseases, immunodeficiencies and cancer). It is not inconceivable that basophils and/or their products could be promising therapeutic targets for such disorders.

The immune network in thyroid cancer

ABSTRACT The immune system plays critical roles in tumor prevention, but also in its initiation and progression. Tumors are subjected to immunosurveillance, but cancer cells generate an immunosuppressive microenvironment that favors their escape from immune-mediated elimination. During chronic inflammation, immune cells can contribute to the formation and progression of tumors by producing mitogenic, prosurvival, proangiogenic and lymphangiogenic factors. Thyroid cancer is the most frequent type of endocrine neoplasia and is the most rapidly increasing cancer in the US. In this review, we discuss recent findings on how different immune cells and mediators can contribute to thyroid cancer development and progression.

Personalized Medicine in Allergy

Allergic disease is among the most common pathologies worldwide and its prevalence has constantly increased up to the present days, even if according to the most recent data it seems to be slightly slowing down. Allergic disease has not only a high rate of misdiagnosis and therapeutic inefficacy, but represents an enormous, resource-absorbing black hole in respiratory and general medicine. The aim of this paper is to summarize principal therapeutic innovations in atopic disease management befallen in the recent years in terms of personalized/precision medicine.

Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors

Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung‐resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2‐arachidonoylglycerol, N‐arachidonoyl‐ethanolamine, N‐palmitoyl‐ethanolamine, and N‐oleoyl‐ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2‐arachidonoylglycerol in a calcium‐dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH‐133 (but not the endogenous agonist 2‐arachidonoylglycerol) markedly inhibits LPS‐induced production of vascular endothelial growth factor‐A, vascular endothelial growth factor‐C, and angiopoietins and modestly affects IL‐6 secretion. No significant modulation of TNF‐α or IL‐8/CXCL8 release was observed. The production of vascular endothelial growth factor‐A by human monocyte‐derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage‐assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer‐associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte‐derived macrophages. Activation of cannabinoid receptors on tissue‐resident macrophages might be a novel strategy to modulate macrophage‐assisted vascular remodeling in cancer and chronic inflammation.

From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A translational overview

Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.