Publications by authors named "Francesca Nencini"

28 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1744666X.2020.1860755DOI Listing
January 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17512433.2020.1772053DOI Listing
January 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.

View Article and Find Full Text PDF

Download full-text PDF

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

A severe adverse reaction to omalizumab therapy in chronic spontaneous urticaria.

Dermatol Ther 2020 01 28;33(1):e13204. Epub 2019 Dec 28.

Department of Dermatology, University of Rome "Sapienza", Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dth.13204DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1744666X.2020.1684264DOI Listing
December 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.03113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336713PMC
October 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:

View Article and Find Full Text PDF

Download full-text PDF

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986952PMC
August 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2018.04.007DOI Listing
November 2019

IL-10-Producing Infliximab-Specific T Cells Regulate the Antidrug T Cell Response in Exposed Patients.

J Immunol 2017 08 17;199(4):1283-1289. Epub 2017 Jul 17.

Unit of Immunoallergology, Careggi University Hospital, Careggi, Florence, 50134 Italy; and.

Infliximab (IFX) is a chimeric mAb that can lead to the appearance of anti-drug Abs. Recent research has identified the presence of circulating IFX-specific T cells in treated patients. The aim of the study was to analyze the functional characteristics of IFX-specific T cells, in particular their capability to produce biologically active regulatory cytokines. Drug-stimulated PBMCs or coculture systems were used to detect memory T cells in treated patients. The cytokines produced by IFX-specific T cells, T cell lines, and T cell clones were evaluated at the mRNA and protein levels. Drug infusion induced an increase in IL-10 serum levels in vivo, whereas other cytokines were unchanged. IL-10 mRNA was higher in IFX-stimulated PBMCs from treated patients compared with untreated patients. When analyzed longitudinally, an early IL-10 mRNA expression was observed. HLA class II-restricted IL-10 production by drug-specific T cells from exposed patients was observed in different experimental settings, such as a coculture system, sorted CD154 T cells, IFX peptide-stimulated PBMCs, and IFX-specific T cell clones. Finally, IL-10-producing drug-specific T cell clones downregulated the response of autologous effector T cells to IFX. Overall, these findings identify IFX-specific T cells as a source of biologically active IL-10 and suggest interference by IL-10-producing cells in the detection of drug-specific T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1700008DOI Listing
August 2017

An overview on safety of monoclonal antibodies.

Curr Opin Allergy Clin Immunol 2016 12;16(6):576-581

aImmunoallergology Unit, AOU Careggi bDepartment of Experimental and Clinical Medicine, Centre of Excellence DENOTHE, University of Florence, Florence, Italy.

Purpose Of Review: Biological agents have been a treatment option for many chronic immune-mediated diseases as well as oncological conditions. The issue of infusion reactions is of particular importance and at least in some cases related to the immunogenicity of these drugs with the production of antidrug antibodies. Infectious diseases are a well described side-effect of certain biological agents, even if, at least regarding the biological agents used for the treatment of allergic diseases and immune-mediated diseases, the risk has been reduced. Biological agents clearly impact the physiological functions of the immune system also those connected to immunosurveillance against cancers. This review discusses the safety profile to the main biological agents currently in use in allergic and chronic immune-mediated diseases.

Recent Findings: By reducing chronic inflammation in immune-mediated diseases, biological agents decrease mortality, cardiovascular events without increasing significantly the risk of cancer. In addition, specific clinical procedure enables the identification of potentially reactive patients and the prevention of acute severe reactions. Overall, the ratio between therapeutic and side-effects is clearly in favor of the former.

Summary: The safety profile of biological agents is, just as much as their efficacy, one of the fundamental criteria justifying their clinical broad use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ACI.0000000000000315DOI Listing
December 2016

How the immune system responds to therapeutic biological agents.

J Int Med Res 2016 Sep;44(1 suppl):38-42

Department of Biomedicine, Immunoallergology Section, AOU Careggi, University of Florence, Florence, Italy.

Biological agents target disease mechanisms and have modified the natural history of several immune-mediated disorders. Biological agents are structurally immunogenic, and therefore usually elicit a minor, subclinical and transient phenomenon. Occasionally, however, these drugs induce complete cellular and humoral immune responses, with the main clinical consequences being hypersensitivity reactions or loss of treatment response. This article considers the relative pathogenic mechanisms influencing immunogenicity in biological agents and discusses mechanisms of tolerance and adaptive immune response, including adaptive T-regulatory cell induction and immune response induction. Methods of determining cellular and humoral immune response to biological agents are identified and examined. Assays to detect antidrug antibodies and their isotypes can assist in monitoring immunogenicity and in preventing adverse events. Such strategies also enable resource conservation and may provide regulatory authorities with new insights that can be useful during the process of approving new biological or biosimilar agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0300060515593248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536528PMC
September 2016

Dermatophagoides pteronyssinus group 2 allergen bound to 8-OH modified adenine reduces the Th2-mediated airway inflammation without inducing a Th17 response and autoimmunity.

Mol Immunol 2016 09 29;77:60-70. Epub 2016 Jul 29.

Immunoallergology Unit, Dept. of Biomedicine, Careggi Hospital, Florence, Italy. Electronic address:

8-OH modified adenine bound to Dermatophagoides pteronyssinus group 2 (nDer p2-Conj), a novel allergen-TLR7 agonist conjugate, improves murine airway inflammation in priming and therapeutic settings, however no data are known on the activity of this construct on Th17 cells. The aim of the study was to evaluate if nDer p2-Conj elicited in vivo Th17 cells and Th17-driven autoimmune responses, by using both short- and long-term priming and therapeutic protocols in a nDer p2-driven model of murine airway inflammation. The conjugate induced the in vitro production of cytokines favouring the Th17 polarization by bone marrow-derived dendritic cells. In short-term protocols, the priming or treatment with the conjugate ameliorated the airway inflammation by shifting Th2 allergen-specific cells into T cells producing IFN-γ, IL-10, but not IL-17A. Similar results were found in long-term protocol where the conjugate down-regulated airway inflammation without any evidence of autoimmune response and B cell compartment expansion. nDer p2-Conj also failed to shorten the spontaneous onset of diabetes on conjugates-primed NOD/LtJ mice. We found that neutrophils in BALF, ROR-γt and IL-17A expression in lungs were increased in conjugate-treated IL-10KO mice. These data emphasize the role of conjugate-driven IL-10 production, which can regulate the activity of memory Th17 cells and prevent the onset of autoimmune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molimm.2016.07.011DOI Listing
September 2016

Treatment with 8-OH-modified adenine (TLR7 ligand)-allergen conjugates decreases T helper type 2-oriented murine airway inflammation.

Immunology 2015 Aug 8;145(4):570-82. Epub 2015 Jun 8.

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

A strategy to improve allergen-specific immunotherapy is to employ new adjuvants stably linked to allergens. The study is addressed to evaluate the in vivo and in vitro effects of allergens [natural Dermatophagoides pteronyssinus 2 (nDer p 2) and ovalbumin (OVA)] chemically bound to an 8-OH-modified adenine. Humoral and cellular responses were analysed in allergen-sensitized and challenged mice by using conjugates (Conj) in a therapeutic setting. The in vitro activity of the conjugates on cytokine production induced by bone marrow dendritic cells and the co-culture system was also investigated. The nDer p 2-Conj treatment in nDer p 2-primed and challenged BALB/c mice reduced the numbers of eosinophils in bronchoalveolar lavage fluid and lung, airway allergen-driven interleukin-13 (IL-13) production in lung mononuclear cells and IgE, in comparison with nDer p 2-treated mice. The increase of IgG2a paralleled that of interferon-γ (IFN-γ) and IL-10 in allergen-stimulated spleen cells. Similar effects were elicited by treatment with OVA-Conj in an OVA-driven BALB/c model. The nDer p 2-Conj or OVA-Conj redirected memory T helper type 2 cells towards the production of IL-10 and IFN-γ also in C57BL/6 mice and when subcutaneously administered. Interleukin-10, IL-12 and IL-27 were produced in vitro by Conj-stimulated bone marrow dendritic cells, whereas IL-10 and IFN-γ were up-regulated in co-cultures of CD11c(+) and CD4(+) T cells from Conj-treated mice stimulated with allergen. Cytofluorometric analysis indicated that the Conj expanded IFN-γ- and IL-10- producing memory T cells. The Conj effects on IL-10(-/-) and IL-12(-/-) mice confirmed the role of IL-10 and IFN-γ in inducing a protective and balanced redirection the T helper type 2-mediated airway inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515136PMC
August 2015

Manifestations of Antidrug Antibodies Response: Hypersensitivity and Infusion Reactions.

J Interferon Cytokine Res 2014 Dec;34(12):946-952

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

Immunogenicity of biological agents leads to the development of antidrug antibodies (ADA) and it may be associated to hypersensitivity reactions. Immediate infusion reactions occur during or within 1 h after infusion, and their clinical manifestations vary considerably, ranging from mild to severe and life-threatening. Recent studies show that different mechanisms sustain hypersensitivity reactions toward biologics, and the application of novel methods for detecting ADA has demonstrated the involvement of specific IgE isotypes. Considering the severity of the reactions, it is important for clinicians to recognize their symptoms, to know their pathophysiological mechanisms, and to take risk assessment and prophylactic procedures. This review summarizes the clinical manifestations of antibody and nonantibody-mediated reactions as well as the humoral and cellular mechanisms of antidrug responses. Last, the management of patients at risk is discussed. The definition of diagnostic and prophylactic strategies represents an unavoidable need in the management of potentially reactive patients to improve the safety profile of biologics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jir.2012.0139DOI Listing
December 2014

Assays and strategies for immunogenicity assessment of biological agents.

Drug Dev Res 2014 Nov;75 Suppl 1:S4-6

Center for Research, Transfer and High Education DENOTHE, University of Florence, Florence, 50134, Italy.

Some patients with chronic inflammatory diseases either do not respond to or lose their initial responsiveness to Tumor Necrosis Factor (TNF) inhibitor therapy. In these patients, the clinical response after switching to another anti-TNF drug suggests that lack of response is not related to the therapeutic target itself but immunogenicity. All biologics are potentially immunogenic and can induce the development of antidrug antibodies (ADAs). ADA formation is associated with lower serum drug levels, infusion reactions, and loss of response. Analytical methods for ADA detection include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), surface plasmon resonance, and electrochemiluminescence. Currently, RIA and ELISA are the preferred methods due to a combination of reproducibility, sensitivity, and cost but have some limitations. There is no single available assay that has all pros and no cons, and therefore the use of more methods for the assessment of samples is a high priority.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ddr.21184DOI Listing
November 2014

Brief report: etanercept inhibits the tumor necrosis factor α-driven shift of Th17 lymphocytes toward a nonclassic Th1 phenotype in juvenile idiopathic arthritis.

Arthritis Rheumatol 2014 May;66(5):1372-7

University of Florence, Florence, Italy.

Objective: To evaluate the effects of etanercept on the phenotype of CD4+ T helper lymphocytes from patients with juvenile idiopathic arthritis (JIA).

Methods: We compared the proportions of various Th cell subsets in peripheral blood (PB) from etanercept-treated and untreated JIA patients. An in vitro study was performed on PB mononuclear cells (PBMCs) from 15 children with untreated JIA, in which we evaluated the proliferative response of these cells, as well as their cytokine production profile, in the presence of various stimuli with or without etanercept.

Results: We found lower proportions of CD4+ CD161+ (nonclassic) Th1 lymphocytes in the PB of patients treated with etanercept than in untreated patients. In vitro, etanercept inhibited the proliferative response induced by either polyclonal or recall antigen stimulation of PBMCs. Moreover, etanercept increased the proportion of CD4+CD161+ Th17/Th1 and Th17 cells in vitro while decreasing the proportions of nonclassic Th1 cell subsets, leaving CD4+CD161- (classic) Th1 cells unaffected. We also found that tumor necrosis factor α (TNFα) was able to induce transition of Th17 lymphocytes toward the nonclassic Th1 phenotype in vitro, probably due to the high expression of TNF receptor type II observed in Th17 cells.

Conclusion: We have previously demonstrated the occurrence of a shifting of CD4+CD161+ Th17 cells to the nonclassic Th1 phenotype in children with JIA. The present findings suggest that etanercept can exert its disease-modifying action by interfering with this shifting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.38355DOI Listing
May 2014

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy.

J Allergy Clin Immunol 2013 Jul 14;132(1):84-92. Epub 2013 Mar 14.

Department of Experimental and Clinical Medicine, Centre for Research, Transfer and High Education DENOTHE, University of Florence, Florence, Italy.

Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy.

Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant.

Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of TH-related transcription factors. Lung cells and sera of nDer p 2-Conj-sensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA.

Results: nDer p 2-Conj stimulated IL-12 and IFN-α production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T(H)2-related cytokines and increased IFN-γ levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-γ upregulation together with IgE downregulation, and an increase in allergen-specific IgG(2a) levels in sera. The conjugate exhibited reduced ability to activate human FcεRI(+) cells without inducing T(H)17 cells or autoantibodies.

Conclusions: The codelivery of an allergen with a modified adenine as a conjugate inducing modulatory cytokines from innate cells redirects in vitro and in vivo pathogenic TH2 responses without eliciting harmful effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2013.01.030DOI Listing
July 2013

Drug-specific Th2 cells and IgE antibodies in a patient with anaphylaxis to rituximab.

Int Arch Allergy Immunol 2012 22;159(3):321-6. Epub 2012 Jun 22.

Immunoallergology Unit, Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. vultaggioa @ aou-careggi.toscana.it

Rituximab (RTX) is currently used in the treatment of lymphoproliferative diseases and of several rheumatologic disorders and is a frequent cause of acute infusion reactions, usually classified as cytokine release syndrome (CRS). Some infusion reactions to RTX raise concern for immediate type I hypersensitivity, even if to date RTX-specific IgE antibodies have not been reported. To improve knowledge of the mechanisms of reactions to RTX, we investigated humoral and cellular immune responses to this drug in a patient suffering from rheumatoid arthritis who displayed two immediate infusion-related reactions. RTX-exposed tolerant patients and healthy untreated subjects were used as controls. Non-isotype-specific and IgE anti-RTX antibodies were positive in the serum samples collected from the reactive patient but not in those from the control groups. Only the reactive patient also displayed skin testing positivity with RTX. More importantly, RTX-stimulated peripheral blood mononuclear cells from the reactive patient, but not from the controls, displayed a dose-dependent proliferative response associated with a Th2 cytokine production profile. Our results show the presence of RTX-specific Th2-type cells and IgE antibodies, thus suggesting that type I hypersensitivity may be an additional mechanism to CRS in the development of RTX reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000336839DOI Listing
December 2012

Skin testing and infliximab-specific antibodies detection as a combined strategy for preventing infusion reaction.

Intern Emerg Med 2012 Sep 5;7 Suppl 2:S77-9. Epub 2011 May 5.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11739-011-0611-xDOI Listing
September 2012

The TLR7 ligand 9-benzyl-2-butoxy-8-hydroxy adenine inhibits IL-17 response by eliciting IL-10 and IL-10-inducing cytokines.

J Immunol 2011 Apr 9;186(8):4707-15. Epub 2011 Mar 9.

Immunoallergology Unit, Careggi Hospital, 50134 Florence, Italy.

This study evaluates the ability of a novel TLR7 ligand (9-benzyl-2-butoxy-8-hydroxy adenine, called SA-2) to affect IL-17 response. The SA-2 activity on the expression of IL-17A and IL-17-related molecules was evaluated in acute and chronic models of asthma as well as in in vivo and in vitro α-galactosyl ceramide (α-GalCer)-driven systems. SA-2 prepriming reduced neutrophils in bronchoalveolar lavage fluid and decreased methacoline-induced airway hyperresponsiveness in murine asthma models. These results were associated with the reduction of IL-17A (and type 2 cytokines) as well as of molecules favoring Th17 (and Th2) development in lung tissue. The IL-17A production in response to α-GalCer by spleen mononuclear cells was inhibited in vitro by the presence of SA-2. Reduced IL-17A (as well as IFN-γ and IL-13) serum levels in mice treated with α-GalCer plus SA-2 were also observed. The in vitro results indicated that IL-10 produced by B cells and IL-10-promoting molecules such as IFN-α and IL-27 by dendritic cells are the major player for SA-2-driven IL-17A (and also IFN-γ and IL-13) inhibition. The in vivo experiments with anti-cytokine receptor Abs provided evidence of an early IL-17A inhibition essentially due to IL-10 produced by resident peritoneal cells and of a delayed IL-17A inhibition sustained by IFN-α and IL-27, which in turn drive effector T cells to IL-10 production. These findings suggest that such TLR7 agonist downregulating Th17 (as well as Th2) response has to be considered a valid candidate for novel vaccine formulations in allergy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1002398DOI Listing
April 2011

Modified adenine (9-benzyl-2-butoxy-8-hydroxyadenine) redirects Th2-mediated murine lung inflammation by triggering TLR7.

J Immunol 2009 Jan;182(2):880-9

Center for Research, Transfer and High Education (DENOThe), Department of Internal Medicine, University of Florence, Florence, Italy.

Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-kappaB activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-beta. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.182.2.880DOI Listing
January 2009