Publications by authors named "Enrico Maggi"

127 Publications

Mechanisms of Drug Desensitization: Not Only Mast Cells.

Front Pharmacol 2020 23;11:590991. Epub 2020 Dec 23.

Translational Immunology Unit, Immunology Area, Pediatric Hospital Bambino Gesù, IRCCS, Rome, Italy.

Drug desensitization (DD) allows transient clinical tolerance to the drug in reactive patients and it is frequently and successfully used in the management of both IgE and non IgE-mediated hypersensitivity reactions (HRs). The underlying mechanisms behind this process is not well understood. The desensitization procedure is associated with the inhibition of mast cells degranulation and cytokine production, that, is attributable, at least partially, to the abrogation of Ca2+ mobilization; findings and mouse models of rapid desensitization show that the organization and spatial distribution of actin is critical for Ca2+ mobilization. Some clinical observations may suggest the induction of a longer memory of tolerance by DD and they raise the suspicion that other cells and mechanisms are involved in DD. Some data are emerging about the modifications of immune responses during DD in patients with previous immediate HRs. In particular, an increase of regulatory cytokines, mainly represented by IL-10, has been shown, and more importantly, the appearance of IL-35 producing T regulatory cells has been described during DD. The release of controlled cellular mediators by mast cells over time and the development of the antigen-specific regulation of adaptive response allow to safely and successfully reach the target dose of a first line drug during DD.
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http://dx.doi.org/10.3389/fphar.2020.590991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793680PMC
December 2020

The emerging role of type 2 inflammation in asthma.

Expert Rev Clin Immunol 2021 Jan 17;17(1):63-71. Epub 2020 Dec 17.

Immunoallergology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

: Bronchial asthma (BA) is a chronic airways inflammatory disease. Based on the biological mechanisms that underline the disease, asthma has been classified as type 2 or non-type 2 phenotype.: An emerging role has been identified for group 2 innate lymphoid cells (ILC2s) able to produce the classical type 2 cytokines. The role of Th2 cells and IL-4 is crucial in the pathogenesis of allergic BA as supported by asthma models. IL-13, shares many biological functions with IL-4 such as induction of IgE synthesis and regulation of eosinophil trafficking. However, IL-13 does not induce Th2 cell differentiation. The Authors reviewed evidence on the new concept of type 2 inflammation and the cellular and molecular network behind this process. Literature data in the PubMed were analyzed for peer-reviewed articles published until September 2020.: The current trend is to consider Th2- and ILC2-driven pathways as two separate pathogenic mechanisms, recent data underscore that adaptive Th2- and innate cell responses represent two integrated systems in the production of IL-4, IL-5, and IL-13 leading to the current 'concept' of type 2 inflammation. This review highlights the role of Th2 cells and ILC2 in the recent new concept of type 2 inflammation.
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http://dx.doi.org/10.1080/1744666X.2020.1860755DOI Listing
January 2021

Group 2 Innate Lymphoid Cells: A Double-Edged Sword in Cancer?

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.

Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s.
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http://dx.doi.org/10.3390/cancers12113452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699723PMC
November 2020

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

PLoS Med 2020 10 30;17(10):e1003348. Epub 2020 Oct 30.

CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods And Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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http://dx.doi.org/10.1371/journal.pmed.1003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598520PMC
October 2020

Low-Dose Mepolizumab Effectiveness in Patients Suffering From Eosinophilic Granulomatosis With Polyangiitis.

Allergy Asthma Immunol Res 2020 Sep;12(5):885-893

Immunoallergology Unit, Careggi University Hospital, Florence, Italy.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by multisystemic manifestations including asthma. Mepolizumab (300 mg/4 weeks) has recently been approved for EGPA. However, real-life data are scarce and report experiences with high doses of mepolizumab intravenously administered (750 mg/4 weeks). The aim of our study was to investigate in a real-life setting whether mepolizumab in EGPA patients at low doses would enable us 1) to control asthma symptoms, 2) to obtain oral corticosteroids (OCS) and/or immunosuppressors tapering and 3) to maintain clinical remission and avoid disease relapses. Mepolizumab (100 mg/4 weeks) was subcutaneously administered for 12 months in 18 EGPA patients with uncontrolled severe asthma. Symptoms, annual asthma exacerbation rates, OCS-sparing effects, lung function and eosinophil activation markers were monitored. The proportion of patients with clinical remission or relapse was also evaluated in month 12. A significant decrease in the annual rate of asthma exacerbations in association with significant changes in asthma control were observed. Specifically, 66.6% of the patients experienced no exacerbations during the mepolizumab treatment. Most patients (77.7%) were able to reduce the daily OCS dose by at least 50%. Four patients also stopped cyclosporine A during the study period. No EGPA relapse was observed and a large majority of the patients achieved clinical remission (94.3%). Clinical benefits were paralleled by reduction in blood eosinophils and serum levels of eosinophil activation markers. Low-dose mepolizumab showed clinically relevant benefits in exacerbation rates, asthma symptoms, OCS and immunosuppressive use in EGPA patients. These effects occurred without any EGPA relapse for extrapulmonary manifestations.
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http://dx.doi.org/10.4168/aair.2020.12.5.885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346991PMC
September 2020

Anaphylactic reactions to biological drugs.

Curr Opin Allergy Clin Immunol 2020 08;20(4):346-351

Translational Immunology Unit, Immunology Area, Pediatric Hospital Bambino Gesù, IRCCS, Rome, Italy.

Purpose Of Review: This review summarizes the current knowledge of the pathogenic mechanisms of biologics-induced anaphylaxis, and the diagnostic and prophylactic strategies in the management of potentially reactive patients, to improve the safety profile of biologics.

Recent Findings: The recent knowledge on the topic highlights the involvement of both effector and regulatory mechanisms in the immune response to biological agents. In addition, the impact of biological's immunogenicity on hypersensitivity reactions has been confirmed in a wider number of studies, defining some details about the kinetics of antidrug antibodies development, specifically immunoglobulin G (IgG) and immunoglobulin E (IgE).

Summary: Biological agents may induce anaphylaxis, mainly through the induction of antidrug antibodies. Biologics-related infusion reactions are often clinically consistent with type I hypersensitivity, but IgG antidrug antibodies may also be involved. The immune response toward biologicals is orchestrated by both effector and regulatory T cells. In addition, nonantibody-dependent mechanisms may occur. Among clinicians persists today again a low awareness, not only of the possibility to understand the immunological mechanisms behind anaphylaxis to biologicals but also the opportunity to apply potential strategies for the management of reactive patients aimed to guarantee a safe retreatment.
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http://dx.doi.org/10.1097/ACI.0000000000000666DOI Listing
August 2020

Prompt Predicting of Early Clinical Deterioration of Moderate-to-Severe COVID-19 Patients: Usefulness of a Combined Score Using IL-6 in a Preliminary Study.

J Allergy Clin Immunol Pract 2020 Sep 19;8(8):2575-2581.e2. Epub 2020 Jun 19.

Immunoallergology Unit, Careggi University Hospital, Florence, Italy. Electronic address:

Background: The early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms.

Objective: The aim of our study was to evaluate the usefulness of testing serum IL-6 and other serological and clinical biomarkers, to predict a short-term negative clinical course of patients with noncritical COVID-19.

Methods: A total of 208 patients with noncritical COVID-19 pneumonia at admission were consecutively enrolled. Clinical and laboratory findings obtained on admission were analyzed by using survival analysis and stepwise logistic regression for variable selection. Three-day worsening as outcome in a logistic model to generate a prognostic score was used.

Results: Clinical worsening occurred in 63 patients (16 = died; 39 = transferred to intensive care unit; 8 worsening of respiratory failure). Forty-five of them worsened within 3 days after admission. The risk of clinical worsening was progressively enhanced along with increasing quartiles of IL-6 levels. Multivariate analysis showed that IL-6 (P = .005), C-reactive protein (CRP) (P = .003), and SaO/FiO (P = .014) were the best predictors for clinical deterioration in the first 3 days after admission. The combined score yielded an area under the curve = 0.88 (95% confidence interval: 0.83-0.93). A nomogram predicting the probability of 3-day worsening was generated. The score also showed good performance for 7-day and 14- or 21-day worsening and in predicting death occurring during all the follow-up.

Conclusions: Combining IL-6, CRP, and SaO/FiO in a score may help clinicians to identify on admission those patients with COVID-19 who are at high risk for a further 3-day clinical deterioration.
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http://dx.doi.org/10.1016/j.jaip.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303032PMC
September 2020

Immunogenicity-unwanted immune responses to biological drugs - can we predict them?

Expert Rev Clin Pharmacol 2021 Jan 8;14(1):47-53. Epub 2020 Jun 8.

Immunoallergology Unit, University Hospital Careggi , Florence, Italy.

Introduction: Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved.

Areas Covered: Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity.

Expert Opinion: Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.
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http://dx.doi.org/10.1080/17512433.2020.1772053DOI Listing
January 2021

Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology.

Clin Mol Allergy 2020 6;18. Epub 2020 May 6.

5Section of Dermatology, Department of Medicine, University of Perugia, Perugia, Italy.

Background: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year.

Methods: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria.

Conclusions: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema.
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http://dx.doi.org/10.1186/s12948-020-00123-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201804PMC
May 2020

COVID-19: Unanswered questions on immune response and pathogenesis.

J Allergy Clin Immunol 2020 Jul 8;146(1):18-22. Epub 2020 May 8.

Department of Immunology, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

The novel coronavirus disease 2019 has rapidly increased in pandemic scale since it first appeared in Wuhan, China, in December 2019. In these troubled days the scientific community is asking for rapid replies to prevent and combat the emergency. It is generally accepted that only achieving a better understanding of the interactions between the virus and the host immune response and of the pathogenesis of infection is crucial to identify valid therapeutic tools to control virus entry, replication, and spread as well as to impair its lethal effects. On the basis of recent research progress of severe acute respiratory syndrome coronavirus 2 and the results on previous coronaviruses, in this contribution we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects and host immunity to the virus. On this basis, we also touch important aspects regarding the immune response in asymptomatic subjects, the immune evasion of severe acute respiratory syndrome coronavirus 2 in severe patients, and differences in disease severity by age and sex.
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http://dx.doi.org/10.1016/j.jaci.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205667PMC
July 2020

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor In Exosome-Mediated Cytotoxicity Against Tumor.

Cancers (Basel) 2020 03 12;12(3). Epub 2020 Mar 12.

Immunology Research Area, IRCCS Bambino Gesù Pediatric Hospital, 00146 Rome, Italy.

Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes.
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http://dx.doi.org/10.3390/cancers12030661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140072PMC
March 2020

Siglec-7, a target for novel therapeutical approaches of Systemic Mastocytosis.

Pharmacol Res 2020 08 29;158:104731. Epub 2020 Feb 29.

Department of Immunology, IRCCS Bambino Gesù Children's Hospital, 00146, Roma, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2020.104731DOI Listing
August 2020

Systemic hypereosinophilic syndromes: when autoimmunity is Th2 mediated.

Curr Opin Allergy Clin Immunol 2020 04;20(2):175-180

Immunoallergology Unit, AOU Careggi, University of Florence, Florence.

Purpose Of Review: Clinical conditions associated with hypereosinophilia represent a field of particular interest, taking into account the epidemiological impact of the different primary and secondary forms. In addition to a classical Th1 response, also Th2 cells can be involved in the pathogenesis of autoimmune diseases, among them eosinophilic forms such as eosinophilic granulomatosis with polyangiitis.

Recent Findings: In patients with severe asthma, recent evidence highlights the role of pathogenic autoantibodies against autologous eosinophil proteins (e.g. eosinophil peroxidase) suggest the role of autoimmune mechanisms, particularly in patients in which asthma is included in eosinophilic vasculitis with antineutrophilic autoantibody positivity. Is now evident that in addition to Th2 cells, also type 2 innate lymphoid cells and Th1/Th17 cells play a central role in the pathogenesis of hypereosinophilic syndrome.

Summary: The definition of cellular and molecular mechanisms and the critical role of specific cytokines involved in the pathogenesis of hypereosinophilic syndrome open the way to new therapeutic strategies by using biological agents targeting these specific factors.
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http://dx.doi.org/10.1097/ACI.0000000000000614DOI Listing
April 2020

Desensitization modulates humoral and cellular immune response to infliximab in a patient with an immediate hypersensitivity reaction.

J Allergy Clin Immunol Pract 2020 05 13;8(5):1764-1767.e1. Epub 2020 Jan 13.

Immunoallergology Unit, Department of Medicine and Geriatrics, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1016/j.jaip.2019.12.040DOI Listing
May 2020

Eosinophils, the IL-5/IL-5Rα axis, and the biologic effects of benralizumab in severe asthma.

Respir Med 2019 Nov - Dec;160:105819. Epub 2019 Nov 11.

Immunoallergology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Bronchial asthma is a chronic inflammatory disease characterized, in a percentage of patients, as an eosinophilic inflammation of the airways. Eosinophils are recognized as a proinflammatory granulocyte playing a major role in the T2-high phenotype, which includes severe eosinophilic asthma. Eosinophilic asthma represents the majority of the phenotypic variants clinically characterized by severity and frequent exacerbations. For patients with severe uncontrolled asthma, monoclonal antibodies are used as add-on treatments. Among them, in addition to anti-immunoglobulin E therapy, biologic agents directed toward the interleukin (IL)-5/IL-5Rα axis and, thus, interfering with the pathologic functions of eosinophils, are now available. Unlike the other anti‒IL-5 monoclonal antibodies which exert an indirect effect on eosinophils, benralizumab, an afucosylated IgG kappa antibody directed against the α subunit of IL-5R, directly depletes eosinophils and their associated bone marrow progenitor cells through induction of antibody-dependent cell-mediated cytotoxicity, through recruitment of natural killer cells. This article reviews the role of eosinophils in the pathogenesis of bronchial asthma and discusses the potential advantageous biologic effects of benralizumab in comparison with other monoclonal antibodies targeting the IL-5 ligand.
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http://dx.doi.org/10.1016/j.rmed.2019.105819DOI Listing
August 2020

Hypersensitivity reactions to biologics used in rheumatology.

Expert Rev Clin Immunol 2019 12 30;15(12):1263-1271. Epub 2019 Oct 30.

Immunoallergology Unit, Department of Medicine and Geriatrics, Careggi University Hospital, Florence, Italy.

: Biological agents (BAs) target disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse. In addition, ADAs can also cause serious adverse events such as infusion hypersensitivity reactions (HRs).: This review discusses the recent knowledge on the effector and regulatory mechanisms involved in the immune response to BAs used in patients suffering from rheumatic diseases leading to the production of ADAs and the impact on clinical outcome. Specifically, the demonstration of the involvement of specific T cell responses underlines B cells activation, and ADAs production is discussed correlating them to the different possible clinical consequences.: Although the mechanisms of the immune response and specifically the ADAs production to BAs have been extensively clarified in the last years, as well as their capacity to impact on clinical outcomes, among clinicians today a low awareness and in some cases a rejection persists, not only of the analysis and understanding of the immunological mechanisms behind the immunogenicity of BAs, but also the possible clinical impact that this may have.
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http://dx.doi.org/10.1080/1744666X.2020.1684264DOI Listing
December 2019

The intestinal expansion of TCRγδ and disappearance of IL4 T cells suggest their involvement in the evolution from potential to overt celiac disease.

Eur J Immunol 2019 12 25;49(12):2222-2234. Epub 2019 Oct 25.

Institute of Biochemistry and Cell Biology, National Research Council, Naples, Italy.

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions. Most patients have villous atrophy (overt-CD), while others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analyzed by flow cytometry in gut biopsies of children with overt- or potential-CD and in healthy controls. Density of TCRγδ T cells was found markedly enhanced in intestinal mucosa of children with overt-CD compared to potential-CD or controls. By contrast, very few IL4 T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4 T cells were classical CD4 T-helper cells (CD161 ), producing or not IFN-γ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ T cells, and concomitant disappearance of IL4 cells. These findings suggest that immunomodulatory mechanisms are active in potential-CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4 and TCRγδ T cells as biomarkers of the different CD forms.
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http://dx.doi.org/10.1002/eji.201948098DOI Listing
December 2019

Medroxyprogesterone Acetate Decreases Th1, Th17, and Increases Th22 Responses via AHR Signaling Which Could Affect Susceptibility to Infections and Inflammatory Disease.

Front Immunol 2019 3;10:642. Epub 2019 Apr 3.

Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, United States.

A synthetic progestin, medroxyprogesterone acetate (MPA), was used in a novel study to determine progestin effects on human purified macrophages and Th1, Th2, Th17, Th22 cells. MPA concentrations were equivalent to those in the serum of women after 6 and 9 months of progestin use. MPA has no effect on the proliferation of PBMCs and CD4+ T cell clones induced by immobilized anti-CD3 antibodies or by antigen (streptokinase). However, MPA decreases production and mRNA expression of IL-5, IL-13, IFN-γ, T-bet, RORC, and IL-17A but increases production and mRNA expression of IL-22 by CD4+ Th22 cell clones and decreases IL-22 production by Th17 cells. MPA inhibits RORC, but not T-bet and AHR, by Th17 cells but increases AHR mRNA and T-bet expression of established CD4+ Th22 cell clones. This suggests that MPA, at concentrations equivalent to those found in the serum of women after treatment for contraception and hormone replacement therapy, can directly inhibit Th1 responses (against intracellular bacteria and viruses), Th17 (against extracellular bacteria and fungi), Th2 (against parasites) but MPA therapy increases IL-22 produced by Th22 cells mediated by an increased expression of AHR and T-bet controlling inflammation. MPA could be responsible for the tissue damage limited by IL-22 in absence of IL-17A.
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http://dx.doi.org/10.3389/fimmu.2019.00642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456711PMC
June 2020

Rapid clinical improvement of atopic dermatitis in an Omalizumab treated patient.

Clin Mol Allergy 2019 12;17. Epub 2019 Mar 12.

2Immunoallergology Unit, Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Background: Atopic dermatitis is a chronic inflammatory skin disorder, whose symptoms and severity grossly depend on individual trigger factors. The majority of patients are satisfactorily treated with emollients together with topical and systemic therapies. However, treatment failure or long-term side effects with conventional treatment options can be a significant clinical problem. Recently, novel therapeutic approaches focus on targeting skewed immune responses providing a more effective, and less harmful approach. Among them, variable success has been reported using Omalizumab, when used in combination with classic therapies. This report describes an interesting case of severe adult onset difficult-to-treat atopic dermatitis dramatically improved in response to treatment with Omalizumab.

Case Presentation: We present a case of an adult male with severe allergic atopic dermatitis, with concomitant involvement of the face, neckline, trunk and forearms and systemic symptoms such as diarrhoea with important decrease of his daily quality of life. The patient had been prescribed oral steroids in addition to anti-histamines to no avail. Due to lack of response to classic therapies, strict diet, as well as to treatment with intravenous corticosteroids, an off-label treatment with Omalizumab based on patient weight and total IgE value was proposed. Clear clinical results were observed after only a few weeks with regards to systemic symptoms, and just after 2 months of treatment in regards to skin involvement.

Conclusions: In the majority of treated patients the clinical improvement of cutaneous manifestations is expected after several months of treatment, as skin manifestations are the consequence of a chronic inflammatory process. The outstanding rapid response observed in this case as well as the persistence of the clinical remission suggests that the block of the IgE pathways modulate functions of cells involved in the pathogenic mechanisms of chronic skin inflammation but also in the acute phases observed in the flare-ups of the disease.
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http://dx.doi.org/10.1186/s12948-019-0109-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413441PMC
March 2019

T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis.

Front Immunol 2018 11;9:3113. Epub 2019 Jan 11.

Immunoallergology Unit, Careggi University-Hospital, Florence, Italy.

This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression . The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.
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http://dx.doi.org/10.3389/fimmu.2018.03113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336713PMC
October 2019

Decidual Interleukin-22-Producing CD4+ T Cells (Th17/Th0/IL-22+ and Th17/Th2/IL-22+, Th2/IL-22+, Th0/IL-22+), Which Also Produce IL-4, Are Involved in the Success of Pregnancy.

Int J Mol Sci 2019 Jan 19;20(2). Epub 2019 Jan 19.

Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, 50134 Florence, Italy.

Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In those experiencing successful pregnancy and those experiencing unexplained recurrent abortion (URA), the levels of IL-22 produced by decidual CD4+ T cells are higher than those of peripheral blood T cells. We found a correlation of IL-22 and IL-4 produced by decidual CD4+ T cells in those experiencing successful pregnancy, not in those experiencing URA. The correlation of IL-22 and IL-4 was also found in the serum of successful pregnancy. A prevalence of CD4+ T cells producing IL-22 and IL-4 (Th17/Th2/IL-22+, Th17/Th0/IL-22+, Th17/Th2/IL-22+, and Th0/IL-22+ cells) was observed in decidua of those experiencing successful pregnancy, whereas Th17/Th1/IL-22+ cells, which do not produce IL-4, are prevalent in those experiencing URA. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells are exclusively present at the embryo implantation site where IL-4, GATA-3, IL-17A, ROR-C, IL-22, and AHR mRNA are expressed. T-bet and IFN-γ mRNA are found away from the implantation site. There is no pathogenic role of IL-22 when IL-4 is also produced by decidual CD4+ cells. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells seem to be crucial for embryo implantation.
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http://dx.doi.org/10.3390/ijms20020428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359245PMC
January 2019

The percentage of patients achieving complete remission of urticaria increases with repeated courses of treatment.

J Allergy Clin Immunol Pract 2019 Jan 2;7(1):339-340. Epub 2018 Jul 2.

Immunoallergology Unit, Careggi University Hospital, Florence, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.06.011DOI Listing
January 2019

Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis.

Ann Rheum Dis 2019 04 12;78(4):575-577. Epub 2018 Oct 12.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2018-214240DOI Listing
April 2019

Omalizumab dampens type 2 inflammation in a group of long-term treated asthma patients and detaches IgE from FcεRI.

Eur J Immunol 2018 12 9;48(12):2005-2014. Epub 2018 Oct 9.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

Even if omalizumab is broadly used in the treatment of severe, allergic asthma, the immunological effects in long-term treated patients have not been fully elucidated. To this aim, a cohort of 15 allergic asthmatic patients treated with omalizumab for at least three years was compared with 12 allergic asthma patients treated with standard therapy. Omalizumab treated asthmatic patients showed lower frequencies of circulating plasmacytoid DCs, and lower CD154 expression on CD4 T-helper cells than the control group. Moreover, basophils and DCs from omalizumab-treated patients had lower surface expression of IgE compared to the control group. In a longitudinal evaluation of two patients that started omalizumab treatment, we show that FcεRI free of IgE were evident on basophils just after four weeks of drug administration. Finally, in vitro experiments with basophils obtained from healthy donors confirm that omalizumab is able to detach IgE from high affinity IgE receptors. Collectively these data indicate that long-term omalizumab treatment dampens type 2 inflammation acting on different cell types that play a pivotal role in the pathogenesis of allergic asthma. Moreover, we have identified a further mechanism of action of omalizumab, such as the ability to detach IgE from its receptor.
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http://dx.doi.org/10.1002/eji.201847668DOI Listing
December 2018

Eomes controls the development of Th17-derived (non-classic) Th1 cells during chronic inflammation.

Eur J Immunol 2019 01 22;49(1):79-95. Epub 2018 Nov 22.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Firenze, Italy.

It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR-γt expression can restore or initiate IL-17 expression by non-classic or classic Th1 cells, respectively, while common pro-Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN-γ secretion while inhibiting the expression of ROR-γt and IL-17. By using a mouse model of T cell-dependent colitis we demonstrate that Eomes controls non-classic Th1 cell development also in vivo and promotes their pathogenic potential. Eomes expression associates to a highly inflammatory phenotype also in patients with juvenile idiopathic arthritis. Indeed, it favors the acquisition of a cytotoxic signature, and promotes the development of IFN-γ GM-CSF cells that have been described to be pathogenic in chronic inflammatory disorders.
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http://dx.doi.org/10.1002/eji.201847677DOI Listing
January 2019

[Immunological mechanisms of allergic diseases].

Authors:
Enrico Maggi

G Ital Med Lav Ergon 2017 11;39(3):168-171

Ordinario di Medicina Interna, Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze.

Objectives: In the last decades the knowledge on pathogenetic mechanisms of allergic diseases extraordinarily improved with relevant clinical outputs. From the '90yrs we know that Th2 cells are essential for allergic inflammation, since they produce type 2 cytokines, recognise allergens, induce IgE switch on B cells and recruit mastcells and eosinophils into tissues for maintaining the flogosis.

Methods: Recently a new subset of innate immunity (ILC2) have been shown to amplify the allergic inflammation.

Results: The chronicity of respiratory allergy is characterised by tissue signals which address T cell to a "Th2 high"- (ILC2/Th2 responses) or a "Th2 low" (ILC3/Th17 responses) endotype, with a BAL prevalence of eosinophils or neutrophils, respectively.

Conclusions: This double response is essentially due to T effector cell plasticity, modulated by microenvironmental signals. The discovery of new endotypes, diagnosed by selective biomarkers and cured by biological agents, will open the era of personalised medicine also for respiratory allergic disorders.
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November 2017

Efficacy and Safety of Mepolizumab (Anti-Interleukin-5) Treatment in Gleich's Syndrome.

Front Immunol 2018 29;9:1198. Epub 2018 May 29.

Department of Biomedicine, Immunoallergology Unit, AOU Careggi, Florence, Italy.

Gleich's syndrome (GS) is characterized by recurrent episodes of angioedema, increase in body weight, fever, hypereosinophilia, and elevated serum IgM. The exact etiology remains unclear. Currently, the only treatment strategy is the administration of high dose of steroids during the acute phases. We report the case of a 37-year-old man suffering from GS with recurrent episodes of angioedema, fever, hypereosinophilia [6,000/mm (45%)], and high eosinophil cationic protein (ECP) (>200 μg/l), treated with oral steroids during the acute phase (prednisone 50-75 mg/day), the dose of maintenance being 25 mg/day. No monoclonal components were identified, and genetic tests exclude mutations including Bcr/Abl, JAK2 V617F, c-KIT D816V, and FIP1L1-PDGFRA. Using Luminex technology, we observed higher serum levels of interleukin (IL)-5, CCL2, and CCL11 during the acute exacerbations in comparison with the clinical remission phases though CCL11 did not achieve statistical significance. The flow-cytometric analysis identified a CD3+ CD8- lymphocyte population with high frequency of IL-4-, IL-5-, and IL-13-producing cells. No clinical benefit was observed after therapeutic strategies with imatinib, interferon-α, cyclosporine-A, and azathioprine. Due to high IL-5 serum levels, an intravenous treatment with anti-IL-5 monoclonal antibody mepolizumab (750 mg every 4 weeks) was started. A reduction in the rate of exacerbation phases/year (10 ± 3 vs 2 ± 1;  < 0.005), in the eosinophils count both in percentage (28.8 ± 12.8 vs 9.8 ± 3.9;  < 0.001) and absolute value (2,737 ± 1,946 vs 782 ± 333;  < 0.001) were observed as well as the ECP serum levels (132.7 ± 62.7 vs 21 ± 14.2 μg/l;  < 0.05). The daily dose of prednisone was significantly reduced (25 vs 7.5 mg). Any adverse effects were recorded. To the best of our knowledge, this case is the first report of the disease successfully treated with mepolizumab, and it could represent a novel therapeutic strategy in GS.
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http://dx.doi.org/10.3389/fimmu.2018.01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986952PMC
August 2019

Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question?

Respir Res 2018 06 8;19(1):113. Epub 2018 Jun 8.

Novartis Pharma AG, Basel, Switzerland.

Bronchial asthma (BA) is a chronic inflammatory disease with a marked heterogeneity in pathophysiology and etiology. The heterogeneity of BA may be related to the inducing mechanism(s) (allergic vs non-allergic), the histopathological background (eosinophilic vs non-eosinophilic), and the clinical manifestations, particularly in terms of severity and frequency of exacerbations. Asthma can be divided into at least two different endotypes based on the degree of Th2 inflammation (T2 'high' and T2 'low'). For patients with severe uncontrolled asthma, monoclonal antibodies (mAbs) against immunoglobulin E (IgE) or interleukin (IL)-5 are now available as add-on treatments. Treatment decisions for individual patients should consider the biological background in terms of the "driving mechanisms" of inflammation as this should predict the patients' likely responses to treatment. The question is not whether an anti-IgE or an anti-eosinophilic strategy is more effective, but rather what the mechanism is at the origin of the airway. While IgE is involved early in the inflammatory cascade and can be considered as a cause of allergic asthma, eosinophilia can be considered a consequence of the whole process. This article discusses the different roles of the IgE and IL-5/eosinophil pathways in the pathogenic mechanisms of airway inflammation occurring in allergic asthma, and the possible reasons to choose an anti-IgE mAb or anti-IL-5 treatment.
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http://dx.doi.org/10.1186/s12931-018-0813-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992661PMC
June 2018

The Kinetics of Antidrug Antibodies, Drug Levels, and Clinical Outcomes in Infliximab-Exposed Patients with Immune-Mediated Disorders.

J Allergy Clin Immunol Pract 2018 Nov - Dec;6(6):2065-2072.e2. Epub 2018 Apr 13.

Unit of Immunoallergology, Careggi University Hospital, Florence, Italy.

Background: Hypersensitivity reactions (HRs) and loss of response (LOR) to infliximab (IFX) are related to drug immunogenicity characterized by antidrug antibodies (ADAs).

Objective: To analyze the timing of ADA appearance and its relationship with drug levels and clinical outcomes in IFX-treated patients with different diseases.

Methods: Samples were longitudinally collected before each infusion from 91 IFX-treated patients and were assayed for ADA and drug levels by enzyme-linked immunosorbent assay and for IgE by ImmunoCAP system. Clinical data regarding efficacy and safety of therapy were also monitored.

Results: The ADA onset occured quite early, irrespective of the type of disease, during the first year and more frequently and earlier during the second cycle of therapy. Patients with HR were more frequently ADA-positive and with higher ADA titers compared with other patient groups. ADA onset tends to precede HRs and LOR; all HRs that occur after a period of drug interruption are preceded by ADA development. Before ADA detection, a progressive decline in IFX levels until a complete disappearance was observed. The ADA titer was maintained for years both in patients with ongoing therapy and in those who interrupted it. IgE ADAs are more frequently developed in patients with higher ADA levels and earlier ADA onset, but their rate of negativization is faster.

Conclusion: The present data suggest that most IFX-exposed patients develop ADAs within the first year of treatment irrespective of disease type. The clinical outcome to the treatment is preceded by ADA development, which in turn is associated with the reduction in drug serum levels. Both ADA evaluation and therapeutic drug monitoring may have a relevant impact on clinical practice, giving new insights to predict LOR and HRs.
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http://dx.doi.org/10.1016/j.jaip.2018.04.007DOI Listing
November 2019

Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia - The SCELTA Trial.

Circ J 2018 05 23;82(6):1688-1698. Epub 2018 Mar 23.

Careggi University Hospital.

Background: The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14CD34cells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.Methods and Results:ECEPCs (obtained from non-mobilized peripheral blood by immunomagnetic selection of CD14and CD34cells) or BM-MNC were injected into the gastrocnemius of the affected limb in 23 and 17 patients, respectively. After a mean of 25.2±18.6-month follow-up, both groups showed significant and progressive improvement in muscle perfusion (primary endpoint), rest pain, consumption of analgesics, pain-free walking distance, wound healing, quality of life, ankle-brachial index, toe-brachial index, and transcutaneous PO. In ECEPC-treated patients, there was a positive correlation between injected CD14CD34cell counts and the increase in muscle perfusion. The safety profile was comparable between the ECEPC and BM-MNC treatment arms. In both groups, the number of deaths and major amputations was lower compared with eligible untreated patients and historical reference patients.

Conclusions: This study supports previous trials showing the efficacy of BM-MNC autotransplantation in CLI patients and demonstrates comparable therapeutic efficacy between BM-MNC and EPEPCs.
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http://dx.doi.org/10.1253/circj.CJ-17-0720DOI Listing
May 2018