ABSTRACT
BACKGROUND: Pheochromocytoma is associated with systemic inflammation, but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and haematological parameters - as a surrogate of inflammation - in patients with pheochromocytoma and the influence of preoperative α-blockade treatment. DESIGN AND METHODS: We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age 53 years, 64.7% females) and two control groups matched for age, sex, and body mass index (BMI): 68 patients with non-functioning adrenocortical tumors (NFAT) and 53 with essential hypertension (EAH). The complete blood count (CBC) and several inflammation-based scores [Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic-Immune-Inflammation Index (SII), Prognostic-Nutrition Index (PNI)] were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n=26) and before and after preoperative α-blockade treatment (n=29). RESULTS: A higher inflammatory state, as indicated by both CBC and inflammation-based scores, was observed in patients with pheochromocytoma compared to NFAT and EAH. Plasma metanephrine levels showed a positive correlation with NLR (r=0.4631), PLR (r=0.3174), SII (r=0.3709), and a negative correlation with LMR (r=0.4368) and PNI (r=0.3741), even after adjustment for age, sex, ethnicity, BMI and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (p=0.001), PLR (p=0.003), SII (p=0.004) and a concomitant increase in LMR (p=0.0002). Similarly, α-blockade treatment led to a reduction in NLR (p=0.007) and SII (p=0.03). CONCLUSIONS: Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade.
ABSTRACT
OBJECTIVE: Benign adrenocortical tumours are diagnosed in â¼5% of adults and are associated with cortisol excess in 30%-50% of cases. Adrenal Cushing's syndrome (CS) is rare and leads to multiple haematological alterations. However, little is known about the effects of the much more frequent mild autonomous cortisol secretion (MACS) on immune function. The aim of this study was to evaluate the haematological alterations in benign adrenocortical tumours with different degrees of cortisol excess. DESIGN AND METHODS: We investigated 375 patients: 215 with non-functioning adrenal tumours (NFAT), 138 with MACS, and 22 with CS. We evaluated the relationship between the degree of cortisol excess and full blood count as well as multiple inflammation-based scores, including the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), and the systemic immune-inflammation index (SII). RESULTS: We observed a gradual and significant increase of leucocytes, neutrophils, and monocytes across the spectrum of cortisol excess, from NFAT over MACS to CS. Neutrophil-to-lymphocyte ratio and SII were significantly higher in both MACS and CS when compared to NFAT (P < .001 and P = .002 for NLR and P = .006 and P = .021 for SII, respectively). Conversely, LMR was lower in MACS and CS than in NFAT (P = .01 and <.001, respectively) but also significantly lower in CS compared to MACS (P = .007). CONCLUSIONS: Neutrophil-to-lymphocyte ratio, SII, and LMR correlated with the degree of cortisol excess in benign adrenocortical tumours and were altered in patients with CS and MACS. These findings suggest that, similar to clinically overt CS, MACS also affects the immune function, potentially contributing to the MACS-associated comorbidities.
Subject(s)
Adrenal Cortex Neoplasms , Adrenal Gland Neoplasms , Cushing Syndrome , Adult , Humans , Hydrocortisone , Cushing Syndrome/diagnosis , Retrospective Studies , Adrenal Gland Neoplasms/pathology , InflammationABSTRACT
BACKGROUND AND AIM: Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS. METHODS: Seventeen patients undergoing surgical excision of VS were recruited into the study. Reverse transcription with quantitative polymerase chain reaction (RT-qPCR) was performed on VS tissue samples and fibroblast-associated molecules examined. Immunofluorescence and immunohistochemistry in VS tissue were used to study the expression of fibroblast markers CD90 and podoplanin in situ. Fibroblast cultures were established from VS, and RT-qPCR analysis was performed on a panel of fibroblast markers on VS and control tissue fibroblasts. RESULTS: Several fibroblast-associated molecules including members of galectin family and matrix metalloproteinases were found to be expressed in VS tissue on RT-qPCR analysis. In situ, expression of CD90 and podoplanin was observed in VS tissue both on immunohistochemistry and immunofluorescence. RT-qPCR analysis of fibroblasts from VS and control vestibular neuroepithelium (NE) showed a higher expression of several molecules of the galectin and matrix metalloproteinases family on VS fibroblasts compared with NE fibroblasts. CONCLUSION: This work examines fibroblasts from VS and shows qualitative differences from NE fibroblasts on RT-qPCR. Further understanding of the fibroblast function in the progression of VS will potentially unveil new targets to manage VS growth.
Subject(s)
Neuroma, Acoustic , Humans , Neuroma, Acoustic/pathology , Fibroblasts/metabolism , Matrix Metalloproteinases/metabolism , Galectins/metabolismABSTRACT
Introduction: The synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters. Methods: Synovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets. Results: We show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion. Discussion: In this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.
Subject(s)
Arthritis, Rheumatoid , Lactic Acid , Humans , Interleukin-6 , Fibroblasts , InflammationABSTRACT
Fibroblasts, derived from the embryonic mesenchyme, are a diverse array of cells with roles in development, homeostasis, repair, and disease across tissues. In doing so, fibroblasts maintain micro-environmental homeostasis and create tissue niches by producing a complex extracellular matrix (ECM) including various structural proteins. Although long considered phenotypically homogenous and functionally identical, the emergence of novel technologies such as single cell transcriptomics has allowed the identification of different phenotypic and cellular states to be attributed to fibroblasts, highlighting their role in tissue regulation and inflammation. Therefore, fibroblasts are now recognised as central actors in many diseases, increasing the need to discover new therapies targeting those cells. Herein, we review the phenotypic heterogeneity and functionality of these cells and their roles in health and disease.
Subject(s)
Fibroblasts , Inflammation , Humans , Fibroblasts/metabolism , Inflammation/metabolism , Extracellular Matrix/metabolism , Aging , HomeostasisABSTRACT
OBJECTIVES: Given the similarity in symptoms between primary Sjogren's syndrome (SjS) and non-SjS sicca syndrome (sicca), we sought to characterise clinical and proteomic predictors of symptoms in both groups in order to better understand disease mechanisms and help guide development of immunomodulatory treatments. These have not, to date, unequivocally improved symptoms in SjS clinical trials. METHODS: Serum proteomics was performed using O-link inflammation and cardiovascular II panels. SjS (n=53) fulfilled 2016 ACR/European Alliance of Associations for Rheumatology (EULAR) criteria whereas sicca (n=60) were anti-Ro negative, displayed objective or subjective dryness, and either had a negative salivary gland biopsy or, in the absence of a biopsy, it was considered that a biopsy result would not change classification status. Linear regression analysis was performed to identify the key predictors of symptoms. Cluster analysis was completed using protein expression values. RESULTS: EULAR-Sjögren's-Syndrome-Patient-Reported-Index (ESSPRI), EuroQoL-5 Dimension utility values, and anxiety and depression did not differ between SjS and sicca. Correlations between body mass index (BMI) and ESSPRI were found in sicca and to a lesser extent in SjS. Twenty proteins positively associated with symptoms in sicca but none in SjS. We identified two proteomically defined subgroups in sicca and two in SjS that differed in symptom burden. Within hierarchical clustering of the SjS and sicca pool, the highest symptom burden groups were the least distinct. Levels of adrenomedullin (ADM), soluble CD40 (CD40) and spondin 2 (SPON2) together explained 51% of symptom variability in sicca. ADM was strongly correlated with ESSPRI (spearman's r=0.62; p<0.0001), even in a multivariate model corrected for BMI, age, objective dryness, depression and anxiety scores. CONCLUSIONS: Obesity-related metabolic factors may regulate symptoms in sicca. Further work should explore non-inflammatory drivers of high symptom burden in SjS to improve clinical trial outcomes.
Subject(s)
Rheumatology , Sjogren's Syndrome , Anxiety/etiology , Extracellular Matrix Proteins/therapeutic use , Humans , Neoplasm Proteins/therapeutic use , Proteomics , Sjogren's Syndrome/complications , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/drug therapyABSTRACT
Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCMHR: 1.05, CI: 1.01−1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Biomarkers , Disease Progression , Humans , Leukocytes, Mononuclear , Monocytes , Retrospective StudiesABSTRACT
Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggesting that disease-associated metabolic changes are long-lasting. We term this phenomenon 'metabolic memory'. We identify changes in cell metabolism after acute TNFα stimulation across disease groups. When compared to FLS from patients with early rheumatoid arthritis, FLS from patients with resolving synovitis have significantly elevated mitochondrial respiratory capacity in the resting state, and less fragmented mitochondrial morphology after TNFα treatment. Our findings indicate the potential to restore cell metabotypes by modulating mitochondrial function at sites of inflammation, with implications for treatment of RA and related inflammatory conditions in which fibroblasts play a role.
Subject(s)
Arthritis, Rheumatoid/immunology , Fibroblasts/immunology , Inflammation/immunology , Synoviocytes/immunology , Tumor Necrosis Factor-alpha/metabolism , Adult , Aged , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Cells, Cultured , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Male , Middle Aged , Oxidative Phosphorylation , Regression Analysis , Synoviocytes/metabolism , Synoviocytes/pathology , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive symmetric inflammation of the joints resulting in bone erosion and cartilage destruction with a progressive loss of function and joint deformity. An increased number of findings support the role of innate immunity in RA: many innate immune mechanisms are responsible for producing several cytokines and chemokines involved in RA pathogenesis, such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6, and IL-1. Pattern recognition receptors (PRRs) play a crucial role in modulating the activity of the innate arm of the immune response. We focused our attention over the years on the expression and functions of a specific class of PRR, namely formyl peptide receptors (FPRs), which exert a key function in both sustaining and resolving the inflammatory response, depending on the context and/or the agonist. We performed a broad review of the data available in the literature on the role of FPRs and their ligands in RA. Furthermore, we queried a publicly available database collecting data from 90 RA patients with different clinic features to evaluate the possible association between FPRs and clinic-pathologic parameters of RA patients.
Subject(s)
Arthritis, Rheumatoid/etiology , Immunity, Innate , Receptors, Formyl Peptide/immunology , Receptors, Pattern Recognition/immunology , Arthritis, Rheumatoid/pathology , Humans , Interleukin-6 , Tumor Necrosis Factor-alphaABSTRACT
Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.
Subject(s)
Arthritis/immunology , Insulin/immunology , Signal Transduction/physiology , Animals , Arthritis/metabolism , Humans , Insulin/metabolism , Receptor, Insulin/immunology , Receptor, Insulin/metabolismABSTRACT
The role of metabolic reprogramming in the coordination of the immune response has gained increasing consideration in recent years. Indeed, it has become clear that changes in the metabolic status of immune cells can alter their functional properties. During inflammation, T cells need to generate sufficient energy and biomolecules to support growth, proliferation, and effector functions. Therefore, T cells need to rearrange their metabolism to meet these demands. A similar metabolic reprogramming has been described in endothelial cells, which have the ability to interact with and modulate the function of immune cells. In this overview, we will discuss recent insights in the complex crosstalk between endothelial cells and T cells as well as their metabolic reprogramming following activation. We highlight key components of this metabolic switch that can lead to the development of new therapeutics against chronic inflammatory disorders. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
Subject(s)
Endothelial Cells , T-Lymphocytes , Humans , Inflammation/drug therapyABSTRACT
To study incidence, prevalence and mortality of systemic sclerosis (SSc) in Italy, assessing epidemiological differences between men and women and in distinct age groups. We performed a nationwide population-based study using administrative health data from regional co-payment exemption registries. Patients entitled with SSc-specific co-payment exemption were included. Fourteen of the 20 Italian regions contributed data covering a population of over 45 million individuals. Crude annual incidence rate, annual prevalence, crude annual mortality rate and standardised mortality ratio (SMR) were calculated. In 2016, the overall crude incidence rate of SSc was 18.5 (95% CI 16.9-20.2) per million per year. Incidence rate was 31.0 (95% CI 28.1-34.1) per million in women, and 4.3 (95% CI 3.2-5.6) per million in men. Peak incidence was observed in the age range 55-69 years. Overall annual prevalence was 306.1 (95% CI 301.1-311.2) per million. Prevalence was 530.8 (95% CI 521.5-540.2) per million in women and 67.8 (95% CI 64.4-71.3) per million in men, with a female to male ratio of 7.8:1. Highest prevalence was observed in the range 70-84 years. Crude annual mortality rate was 27.9 (95% CI 24.9-31.1) per 1000 patients. Overall SMR in patients with SSc was 2.8 (95% CI 1.9-3.8). SMR was 3.8 (95% CI 2.9-5.1) in men and 2.6 (95% CI 1.8-3.6) in women. We provided updated estimates on epidemiology of SSc in Italy. Our findings on incidence, prevalence and mortality of SSc are consistent with previously published literature.
Subject(s)
Scleroderma, Systemic/mortality , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Epidemiologic Studies , Female , Humans , Incidence , Italy/epidemiology , Male , Middle Aged , Prevalence , RegistriesABSTRACT
The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
Subject(s)
Inflammation/immunology , Lactic Acid/metabolism , Neoplasms/immunology , Tumor Microenvironment/immunology , Biological Availability , Carrier Proteins/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Membrane Proteins/metabolism , Neoplasms/pathology , Thyroid Hormones/metabolism , Thyroid Hormone-Binding ProteinsABSTRACT
Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipo-cytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.
ABSTRACT
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.
ABSTRACT
It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate-induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti-tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism.
Subject(s)
Lactic Acid/metabolism , Glucose/metabolism , Humans , Inflammation/metabolism , Inflammation/pathology , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Signal TransductionABSTRACT
CD40 and its ligand CD40L (CD154) belong to the tumor necrosis factor receptor superfamily and are expressed by a variety of immune and non-immune cells. CD40L plays a central role in co-stimulation and regulation of the immune response via activation of cells expressing CD40. Imbalance of the CD40-CD40L co-stimulatory pathway has been reported in many autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome, thus supporting its role in the breach of immune tolerance that is typical of these diseases. Targeting CD40-CD40L signalling might represent a novel therapeutic option for several autoimmune disorders.
ABSTRACT
Approximately 5-10% of asthmatic patients worldwide suffer from severe asthma. Experimental and clinical studies have demonstrated that IL-13 is an important cytokine in chronic airways inflammation. IL-13 is involved in Th2 inflammation and has been identified as a possible therapeutic target in the treatment of asthma. Two different human monoclonal antibodies (mAbs) anti-IL-13 (tralokinumab and lebrikizumab) block binding and signaling of IL-13 to its receptors, IL-13Rα1 and IL-13Rα2. Several randomized, double-blind, placebo-controlled multicenter studies have evaluated the safety and efficacy of tralokinumab and lebrikizumab in the treatment of adult patients with severe asthma, but all have failed to meet their primary endpoints. No serious adverse events related to the treatment with these anti-IL-13 mAbs have been reported in these studies. These negative clinical results contrast with positive findings from blocking IL-13 signaling in experimental models of asthma, raising doubts about the transferrable value of some models. Interestingly, dupilumab, a mAb which blocks both IL-4 and IL-13 signaling reduces exacerbation rates and improves lung function in severe asthmatics. These results suggest that IL-4 and IL-13 share some, but not all functional activities in airway inflammation. Tralokinumab might show efficacy in a highly selected cohort of asthmatics characterized by overexpression of IL-13.