Andrea Matucci

Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4

BACKGROUND IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders. OBJECTIVE Study of the relationship between human IL-17A-producing CD4(+) T(H) cells (T(H)17) and IL-4-producing CD4(+) T(H) (T(H)2) cells. METHODS T-cell clones generated from the CCR6(+)CD161(+) fraction of human circulating CD4(+) T cells, which contains virtually all T(H)17 cells, as well as circulating CD4(+) T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile. RESULTS A small proportion of CCR6(+)CD161(+)CD4(+) T-cell clones showed the ability to produce both IL-17A and IL-4 (T(H)17/T(H)2). T(H)17/T(H)2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few T(H)17/T(H)2 cells were found among circulating CD4(+) T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. T(H)17/T(H)2 cells could not be derived from naive umbilical cord blood CD4(+) T cells under any experimental condition. However, when circulating memory CCR6(+)CD161(+)CD4(+) T cells were cloned under appropriate polarizing conditions, T(H)17/T(H)2 clones originated in the presence of IL-4, suggesting that an IL-4-rich microenvironment may induce the shifting of memory T(H)17 cells into T(H)17/T(H)2 cells. CONCLUSION Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of T(H)17/T(H)2 cells may play some role in the pathogenesis of this disease.

Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions.

To cite this article: Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, Romagnani S, Maggi E. Anti‐infliximab IgE and non‐IgE antibodies and induction of infusion‐related severe anaphylactic reactions. Allergy 2010; 65: 657–661.

The importance of Th2‐like cells in the pathogenesis of airway allergic inflammation

During the last 20 years a great research efFort has been made to clarify the complex mechanisms which regulate IgE antibody production. In this regard substantial progress has been made since it was shown that IL-4 and T/B-cell interactions are essential for the induction of human TgE synthesis, whereas IFN-y plays a negative regulatory role. However., more recently it has become quite clear that the reaction of inhaled allergens with IgE specific antibodies bound to Fĉ ^Rl receptors on the surface of mast cells and basophils and the subsequent release of traditional mediators is not sufficient per se to account for the persistent histological,, pathophysiological and clinical alterations that characterize the allergic respiratory disorders. In this connection it has been reasonable to address studies on the possible involvement of other kinds of cells such as, for example,, T-cells,, and of other mediators, such as cytokines.

Acute infusion reactions induced by monoclonal antibody therapy

This article reports recent evidence on epidemiological data concerning monoclonal antibody (mAb) infusion-related anaphylaxis, as well as recent data on the correlation between mAb immunogenicity and safety profiles. Pathogenic mechanisms of mAb-related adverse reactions including hypersensitivity, IgE- and non-IgE-mediated events and cytokine release syndrome are also highlighted. Finally, the role of serum anti-mAb antibodies as markers to monitor the safety of such therapeutical compounds are extensively evaluated. The anaphylaxis occurring during therapy with the anti-TNF-α mAb infliximab, largely used in immune-mediated diseases, has been taken as a paradigm

The thiol redox state of lymphoid organs is modified by immunization: Role of different immune cell populations†

Resting T lymphocytes can internalize reduced cysteine (Cys) but not cystine, the oxidized form of the amino acid that predominates extracellularly. In vitro studies have shown that DC provide Cys to T cells during antigen presentation, allowing their activation. Here, we show that increased thiol production is a hallmark of immune response in vivo. Indeed, the thiol content of LN increases dramatically after antigen injection. Non‐protein thiols co‐distribute with DC and are highly abundant in germinal centers. In agreement, activated but not resting B lymphocytes and macrophages release free thiols. Increased thiol release following activation requires thioredoxin and is paralleled by increased thioredoxin expression. The T zones of LN are consistently less stained, and both resting and activated T cells are unable to release thiols. Interestingly, the cystine/glutamate transporter x  c− is absent in resting T lymphocytes but is rapidly induced by TCR triggering in vitro, indicating that the release of T cells from the need of exogenous Cys occurs early after activation. These results indicate that a reducing microenvironment is essential to start the immune response but dispensable for its evolution, and support the emerging concept that extracellular redox is implicated in the control of crucial cellular functions.

Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management.

Purpose of reviewThe rapid expansion of the use of biologics has resulted in an increase in adverse drug reactions, some of which can be life-threatening, due to the immunogenicity of these new drugs. This review summarizes the current knowledge of the pathogenic mechanisms of biologics-induced hypersensitivity reactions and highlights the most useful diagnostic and prophylactic tools now available in the clinical management of immunogenicity associated with biologics. Recent findingsOver the last few years, many drug-related or patient-related factors contributing to the immunogenicity of biologics have been identified, thus allowing a better identification of patients at risk of reaction. Recent studies show that different mechanisms sustain hypersensitivity reactions toward biologics, and the application of novel methods for detecting antidrug antibodies has allowed the involvement of specific IgE isotypes. Additionally, experience with procedures of desensitization to biologics continues to grow. SummaryConsidering the increased use of the biological therapies in different clinical conditions, the definition of diagnostic and prophylactic strategies represents an unavoidable necessity in the management of potentially reactive patients in order to improve the safety profile of biologics.

Tako-Tsubo-like syndrome during anaphylactic reaction

Tako‐Tsubos syndrome (apical ballooning or broken heart syndrome) is a reversible left ventricular dysfunction due to apical asynergy that occurs typically after sudden emotional stress in a subject without coronary disease. It is characterized by acute onset of chest pain or dyspnoea or both and is associated with electrocardiographic changes such as ST segment elevation and/or T wave inversion. Myocardial biomarkers may be normal or slightly elevated.

Guidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice

Since the introduction of biologics for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis (Pso) an increased risk of tuberculosis (TB) reactivation in patients with latent tuberculosis infection (LTBI) has been recorded for anti-TNF agents, while a low or absent risk is associated with the non-anti-TNF targeted biologics. To reduce this risk several recommendation sets have been published over time, but in most of them the host-related risk, and the predisposing role to TB reactivation exerted by corticosteroids and by the traditional disease-modifying anti-rheumatic drugs has not been adequately addressed. Moreover, the management of the underlying disease, and the timing of biologic restarting in patients with TB occurrence have been rarely indicated. A multidisciplinary expert panel, the Italian multidisciplinary task force for screening of tuberculosis before and during biologic therapy (SAFEBIO), was constituted, and through a review of the literature, an evidence-based guidance for LTBI detection, identification of the individualized level of risk of TB reactivation, and practical management of patients with TB occurrence was formulated. The literature review confirmed a higher TB risk associated with monoclonal anti-TNF agents, a low risk for soluble receptor etanercept, and a low or absent risk for non-anti-TNF targeted biologics. Considering the TB reactivation risk associated with host demographic and clinical features, and previous or current non-biologic therapies, a low, intermediate, or high TB reactivation risk in the single patient was identified, thus driving the safest biologic choice. Moreover, based on the underlying disease activity measurement and the different TB risk associated with non-biologic and biologic therapies, practical indications for the treatment of RA, PsA, AS, and Pso in patients with TB occurrence, as well as the safest timing of biologic restarting, were provided.

Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab.

The administration of biological agents is potentially affected by IgE‐mediated infusion reactions.

T-cell responses during allergen-specific immunotherapy.

Purpose of reviewAllergen-specific immunotherapy is the only specific, dose-dependent and time-dependent and disease-modifying strategy for the treatment of allergy associated with clinical improvement and biological tolerance which may persist years after discontinuation. Recent findingsSuccessful immunotherapy in respiratory allergy is associated with the immunodeviation of Th2 response to a more protective allergen-specific Th1 cells and with the induction of interleukin-10 (IL-10)/transforming growth factor (TGF)-&bgr;-producing T regulatory cells in blood and inflamed airways. Subcutaneous treatment and sublingual treatments induce similar alterations which are dose-dependent and time-dependent. SummaryThis study provides an update on the immunological T-cell responses during subcutanous immunotherapy and sublingual immunotherapy, giving a unifying view of the redirecting mechanisms and regulating mechanisms elicited by these treatments.