Alessandra Vultaggio

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.

Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss

Development of CD4+ helper T (Th) cells into type 1 (Th1) or type 2 (Th2) effectors can be influenced by hormones enhanced during pregnancy. Progesterone, at concentrations comparable to those found at fetomaternal interface, promotes the production of IL-4 and IL-5, whereas relaxin promotes the production of IFN-gamma by T cells. Furthermore, Th1-type cytokines promote allograft rejection and, therefore, may compromise pregnancy, whereas Th2-type cytokines, which inhibit Th1 responses, may allow allograft tolerance. In addition, T cell production of Leukemia Inhibitory Factor (LIF) and macrophage-stimulating factor (M-CSF), which are essential for embryo implantation and development, are up-regulated by IL-4 and progesterone. Finally, a direct cause-and-effect relationship between the defective production of LIF, M-CSF and Th2-type cytokines by T cells present at feto maternal interface and the pregnancy loss has been observed.

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

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.

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.

Drug-Specific Th2 Cells and IgE Antibodies in a Patient with Anaphylaxis to Rituximab

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.

The TLR7 Ligand 9-Benzyl-2-Butoxy-8-Hydroxy Adenine Inhibits IL-17 Response by Eliciting IL-10 and IL-10–Inducing Cytokines

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.

Detection by Flow Cytometry of ESAT-6- and PPD-Specific Circulating CD4+ T Lymphocytes as a Diagnostic Tool for Tuberculosis

Background: The identification of mycobacteria represents the gold standard in the diagnosis of tuberculosis (TB), but it is not applicable in all patients, and immunological tests, such as the tuberculin skin test (TST), are not specific and sensitive enough. Methods: By flow cytometry, we measured the CD4 T-cell response to purified protein derivative (PPD) and early secretory antigenic target-6 (ESAT-6) protein using the intracellular cytokine staining technique on whole blood samples obtained from active TB (n = 16), latent TB (n = 17), Bacille Calmette-Guérin (BCG)-vaccinated (n = 11) and healthy (n = 10) donors. All the patients were also tested with conventional TST. Results: The identification by flow cytometry of PPD-specific T lymphocytes upon antigen stimulation of whole blood enables the discrimination of active TB, latent TB and BCG-vaccinated subjects from healthy individuals, whereas the ESAT-6 response discriminated active TB from healthy and BCG-vaccinated individuals. Moreover, this test enables identification of active TB patients who were negative on TST and to distinguish between TB and non-typical mycobacteria TB infections. Conclusions: The identification by flow cytometry of antigen-specific T lymphocytes upon antigen stimulation of whole blood has a better positive predictive value than TST, and could represent a further tool in the diagnosis of TB infection.