Human Lung Mast Cells: Therapeutic Implications in Asthma.

Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune system during airway inflammation. Moreover, these cells modulate the activities of several structural cells (i.e., fibroblasts, airway smooth muscle cells, bronchial epithelial and goblet cells, and endothelial cells) in the human lung. These findings indicate that lung mast cells and their mediators significantly contribute to the immune induction of airway remodeling in severe asthma. Therapies targeting mast cell mediators and/or their receptors, including monoclonal antibodies targeting IgE, IL-4/IL-13, IL-5/IL-5Rα, IL-4Rα, TSLP, and IL-33, have been found safe and effective in the treatment of different phenotypes of asthma. Moreover, agonists of inhibitory receptors expressed by human mast cells (Siglec-8, Siglec-6) are under investigation for asthma treatment. Increasing evidence suggests that different approaches to depleting mast cells show promising results in severe asthma treatment. Novel treatments targeting mast cells can presumably change the course of the disease and induce drug-free remission in bronchial asthma. Here, we provide an overview of current and promising treatments for asthma that directly or indirectly target lung mast cells.

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019.

Mast cells are immune cells which have a widespread distribution in nearly all tissues. These cells and their mediators are canonically viewed as primary effector cells in allergic disorders. However, in the last years, mast cells have gained recognition for their involvement in several physiological and pathological conditions. They are highly heterogeneous immune cells displaying a constellation of surface receptors and producing a wide spectrum of inflammatory and immunomodulatory mediators. These features enable the cells to act as sentinels in harmful situations as well as respond to metabolic and immune changes in their microenvironment. Moreover, they communicate with many immune and nonimmune cells implicated in several immunological responses. Although mast cells contribute to host responses in experimental infections, there is no satisfactory model to study how they contribute to infection outcome in humans. Mast cells modulate physiological and pathological angiogenesis and lymphangiogenesis, but their role in tumor initiation and development is still controversial. Cardiac mast cells store and release several mediators that can exert multiple effects in the homeostatic control of different cardiometabolic functions. Although mast cells and their mediators have been simplistically associated with detrimental roles in allergic disorders, there is increasing evidence that they can also have homeostatic or protective roles in several pathophysiological processes. These findings may reflect the functional heterogeneity of different subsets of mast cells.

Autoantibodies to IgE can induce the release of proinflammatory and vasoactive mediators from human cardiac mast cells.

Mast cells are multifunctional immune cells with complex roles in tissue homeostasis and disease. Cardiac mast cells (HCMCs) are strategically located within the human myocardium, in atherosclerotic plaques, in proximity to nerves, and in the aortic valve. HCMCs express the high-affinity receptor (FcεRI) for IgE and can be activated by anti-IgE and anti-FcεRI. Autoantibodies to IgE and/or FcεRI have been found in the serum of patients with a variety of immune disorders. We have compared the effects of different preparations of IgG anti-IgE obtained from patients with atopic dermatitis (AD) with rabbit IgG anti-IgE on the release of preformed (histamine and tryptase) and lipid mediators [prostaglandin D2 (PGD2) and cysteinyl leukotriene C4 (LTC4)] from HCMCs. Functional human IgG anti-IgE from one out of six AD donors and rabbit IgG anti-IgE induced the release of preformed (histamine, tryptase) and de novo synthesized mediators (PGD2 and LTC4) from HCMCs. Human IgG anti-IgE was more potent than rabbit IgG anti-IgE in inducing proinflammatory mediators from HCMCs. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Although functional anti-IgE autoantibodies rarely occur in patients with AD, when present, they can powerfully activate the release of proinflammatory and vasoactive mediators from HCMCs.

Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.

IL-33 and Superantigenic Activation of Human Lung Mast Cells Induce the Release of Angiogenic and Lymphangiogenic Factors.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are strategically located in different compartments of human lung, where they play a role in several inflammatory disorders and cancer. Immunoglobulin superantigens (e.g., protein A of Staphylococcus aureus and protein L of Peptostreptococcus magnus) bind to the variable regions of either the heavy (VH3) or light chain (κ) of IgE. IL-33 is a cytokine expressed by epithelial cells that exerts pleiotropic functions in the lung. The present study investigated whether immunoglobulin superantigens protein A and protein L and IL-33 caused the release of inflammatory (histamine), angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The results show that protein A and protein L induced the rapid (30 min) release of preformed histamine from HLMCs. By contrast, IL-33 did not induce the release of histamine from lung mast cells. Prolonged incubation (12 h) of HLMCs with superantigens and IL-33 induced the release of VEGF-A and VEGF-C. Preincubation with IL-33 potentiated the superantigenic release of histamine, angiogenic and lymphangiogenic factors from HLMCs. Our results suggest that IL-33 might enhance the inflammatory, angiogenic and lymphangiogenic activities of lung mast cells in pulmonary disorders.

HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are involved in chronic pulmonary diseases occurring at high frequency among HIV-infected individuals. Immunoglobulin superantigens bind to the variable regions of either the heavy or light chain of immunoglobulins (Igs). Glycoprotein 120 (gp120) of HIV-1 is a typical immunoglobulin superantigen interacting with the heavy chain, variable 3 (VH3) region of human Igs. The present study investigated whether immunoglobulin superantigen gp120 caused the release of different classes of proinflammatory and immunoregulatory mediators from HLMCs. The results show that gp120 from different clades induced the rapid (30 min) release of preformed mediators (histamine and tryptase) from HLMCs. gp120 also caused the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HLMCs. Incubation (6 h) of HLMC with gp120 induced the release of angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The activating property of gp120 was mediated through the interaction with IgE VH3+ bound to FcεRI. Our data indicate that HIV gp120 is a viral superantigen, which induces the release of different proinflammatory, angiogenic, and lymphangiogenic factors from HLMCs. These observations could contribute to understanding, at least in part, the pathophysiology of chronic pulmonary diseases in HIV-infected individuals.

Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma.

Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.

Prostaglandin D2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives.

INTRODUCTION: Prostaglandin D2 (PGD2) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD2 are mediated by D-prostanoid (DP1), DP2 (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD2 exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP2 receptor antagonists and a small number of DP1 receptor antagonists are being developed for the treatment of allergic disorders. AREAS COVERED: The role of DP2 and DP1 receptor antagonists in the treatment of asthma and allergic rhinitis. EXPERT OPINION: Head-to-head studies that compare DP1 antagonists with the standard treatment for allergic rhinitis are necessary to verify the role of these novel drugs as mono- or combination therapies. Further clinical trials are necessary to verify whether DP2 antagonists as monotherapies or, more likely, as add-on therapies, will be effective for the treatment of different phenotypes of adult and childhood asthma. Long-term studies are necessary to evaluate the safety of targeted anti-PGD2 treatments.

Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

Cardiotoxicity of immune checkpoint inhibitors.

Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis. These inhibitors unleash antitumour immunity, mediate cancer regression and improve the survival in a percentage of patients with different types of malignancies, but can also produce a wide spectrum of immune-related adverse events. Interestingly, PD-1 and PD-L1 are expressed in rodent and human cardiomyocytes, and early animal studies have demonstrated that CTLA-4 and PD-1 deletion can cause autoimmune myocarditis. Cardiac toxicity has largely been underestimated in recent reviews of toxicity of checkpoint inhibitors, but during the last years several cases of myocarditis and fatal heart failure have been reported in patients treated with checkpoint inhibitors alone and in combination. Here we describe the mechanisms of the most prominent checkpoint inhibitors, specifically ipilimumab (anti-CTLA-4, the godfather of checkpoint inhibitors) patient and monoclonal antibodies targeting PD-1 (eg, nivolumab, pembrolizumab) and PD-L1 (eg, atezolizumab). We also discuss what is known and what needs to be done about cardiotoxicity of checkpoint inhibitors in patients with cancer. Severe cardiovascular effects associated with checkpoint blockade introduce important issues for oncologists, cardiologists and immunologists.