Research Vito Sabato

Abstract

The risk of anaphylaxis in primary mast cell disorders (PMCDs) and hereditary alpha tryptasemia (H?T) is only partially determined by the mast cell (MC) burden. The overarching hypothesis of this mandate is that the risk of anaphylaxis in PMCDs and H?T is related to an aberrant MC behavior and relates to an imbalance between activating and inhibitory signals culminating in uncontrolled excessive degranulation of these anaphylaxis effector cells. Research conducted during the previous mandate led to the conclusion that the expression of the high affinity receptor for IgE antibodies (Fc?RI) on MCs, but not the quantitative expression of the mas-related G protein coupled receptor X2 (MRGPRX2) nor the phenotype and function of basophil, play a crucial role in determining the risk of wasp venom anaphylaxis in patients with non-advanced PMCDs. Moreover, our previous studies highlight that, for patients with anaphylaxis, clinical and biochemical predictors of PMCDs are suboptimal. Finally, the association between H?T, morphological abnormal MCs, and MC mediator-related symptoms deserve further investigation. During this mandate we aim at expanding study on phenotypic and behavior of individual MCs and integrate with transcriptome and metabolome profiling from phenotypically different patients. The goal is the identification of specific biomarkers able at discriminating in patients with PMCDs phenotypes with and without anaphylaxis.

Researcher(s)

• Promoter: Sabato Vito
• Fellow: Sabato Vito

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Increasing lines of evidence indicate that mast cells (MC) degranulation from off-target occupation of the Mas-related G protein coupled receptor X2 (MRGPRX2) constitutes a novel endotype of IgE/FcεRI (high affinity receptor for IgE) -independent drug anaphylaxis. However, most of the data have been gathered in mice or in malignant mast cell lines. In contrast to MC, MRPGPRX2 is barely expressed on basophils membrane but quickly upregulated after conditioning. Here we propose exploration of a mixed model based upon cultured human mast cells and human basophils aiming at deciphering MRGRPX2 agonism and antagonims in drug anaphylaxis.

Researcher(s)

• Promoter: Sabato Vito
• Co-promoter: Ebo Didier
• Co-promoter: Hagendorens Margo
• Fellow: Van der Poorten Marie-Line

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

• Promoter: De Schepper Heiko
• Co-promoter: De Winter Benedicte
• Co-promoter: Sabato Vito
• Fellow: Van Malderen Kathleen

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Drug hypersensitivity constitutes a significant health problem with serious consequences of both mis- and overdiagnosis. nfortunately, correct diagnosis of drug hypersensitivity can pose significant challenges, mainly because of our knowledge gaps in the molecular and pathophysiological processes underlying immediate and non-immediate drug hypersensitivity reactions but also, most importantly, because of the unavailability of reliable in vitro tests and uncertainties associated with skin testing 1-3. This "proof-of-concept project" is an apex of our ongoing overarching research on the cellular processes, pathophysiology and diagnosis of immediate drug hypersensitivity reactions resulting from mast cell and basophil degranulation 1-30. Likely, this project will deepen our insights and shift paradigms in the mechanisms that govern mast cell degranulation finally culminating in immediate drug hypersensitivity reactions. However, our proposal primarily focuses on i) the confirmation of our innovative MAT (mast cell activation test) to be a performant diagnostic and ii) to expand capacity of our service platform to offer these tests to colleagues and industry. With respect to the valorisation, this POC-proposal should promote our services and offering our MAT (amongst other diagnostics) to more colleagues and industry. Today, our laboratory has already created a restricted service platform. In other words, this POC-project will not restrict to confirmation of the MAT, but will also invest, via several initiatives, in the expansion and promotion of our services (inter)nationally, application for a full patent, and in the set-up of a business model. In this context, communication of the data, analyses of demands and market studies are critical. Clearly, the potential of the MAT, which we already filed a priority application for and necessitates only patients' sera, is broad. Moreover, preliminary results from our market analysis, and the potential of additional indications, could result in industrial interest and the creation of a spin-off.

Researcher(s)

• Promoter: Ebo Didier
• Co-promoter: Sabato Vito

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Unverified and allergies to penicillins have developed into an epidemic with unacceptable medical and financial consequences. For over two decades numerous efforts have been undertaken to fight this scourge and to promote judicious diagnosis to reduce erroneous avoidance and unnecessary substitutions with less effective, more toxic and costly broad spectrum second-line non-betalactam antibiotics carrying the potential of the emergence of organism resistance and secondary complications. However, old habits die hard and continuous efforts are required to convince patients and their physicians of the consequences of these false allegations and to encourage implementation of correct management protocols. In this project we primarily aim at i) mapping out the prevalence of spurious and genuine penicillin allergy, ii) optimizing diagnostic management of betlactam allergies according to the individual allergy risk status including resolving the conundrum of cross-reactivity between penicillin and other belactams and iii) evaluate the cost-effectiveness of delabelling spurious "penicillin allergy" in unselected or selected populations. Altogether, our data should facilitate introduction of a cost-effective diagnostic and therapeutic algorithms without jeopardizing health of our patients and benefiting antibiotic stewardship.

Researcher(s)

• Promoter: Sabato Vito
• Co-promoter: Hagendorens Margo

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

• Promoter: De Schepper Heiko
• Co-promoter: De Winter Benedicte
• Co-promoter: Sabato Vito
• Fellow: Van Malderen Kathleen

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

IgE-mediated peanut allergy starts with a sensitization phase that is characterized by the production of peanut specific IgE (sIgE) antibodies that can be depicted by peanut immunoassays and/or skin tests. However, the production of these peanut sIgE antibodies is not sufficient for the development of an overt peanut allergy. Actually, many subjects with detectable peanut sIgE antibodies in their serum and/or positive skin test response to peanut do not exhibit clinical manifestations when consuming this legume. The divergence between allergic sensitization and clinically overt allergy not only poses significant diagnostic difficulties but also constitutes a fundamental gap in our knowledge and insights about the complex mechanisms of food allergy and tolerance. Clearly, in prospect for future therapy, better understanding of the underlying (molecular) mechanisms is needed. In this project I will investigate whether the clinical phenotype of peanut sensitization and allergy results from altered basophil responses to stimulation with peanut. More specifically, I will look for alterations in basophilic expression and/or function of three families of functionally distinctive inhibitory receptors, i.e. CD300a, CD32B and Siglec-7, 8 and 9. Obtaining more fundamental insights in the basophil response, may disclose diagnostic but also potential therapeutic targets that have already shown promising preclinical results for various mast cell and basophil associated conditions.

Researcher(s)

• Promoter: Ebo Didier
• Co-promoter: Hagendorens Margo
• Co-promoter: Sabato Vito
• Fellow: Van Gasse Athina

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Anaphylaxis, potentially life-threatening, is one of the principal manifestations of systemic mastocytosis. In these patients anaphylaxis can result from IgEdependent and IgE-independent triggering of mast cells and/or basophils. However, the exact reasons for anaphylaxis in systemic mastocytosis remain a fundamental gap in our knowledge. This gap needs to be filled in order to optimize our patients' care and tailor their individual management. Indeed, the total mast cell burden, hitherto best reflected by the serum tryptase level, does not predict the risk of anaphylaxis nor its clinical outcome. Needless to stress that the uncertainties associated to their condition have a severe impact on the quality-of-life of the patient. Our hypothesis is that the occurrence of anaphylaxis in patients with systemic mastocytosis relates to an imbalance in activating and inhibitory pathways in mast cells and basophils, both critical effector cells of anaphylaxis. For this purpose we will first compare the immunophenotype of mast cells and basophils from patients with systemic mastocytosis with and without anaphylaxis. Secondly, we will study the behaviour of individual cells in response to various combinations of activators and inhibitors. As illustrated by our track-record we believe that this application fits into our overarching research. The Antwerp mastocytosis center will guarantee inclusion of the sufficient numbers of patients and healthy controls.

Researcher(s)

• Promoter: Ebo Didier
• Co-promoter: Berneman Zwi
• Fellow: Sabato Vito

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

IgE-mediated peanut allergy starts with a sensitization phase that is characterized by the production of peanut specific IgE (sIgE) antibodies that can be depicted by peanut immunoassays and/or skin tests. However, the production of these peanut sIgE antibodies is not sufficient for the development of an overt peanut allergy. Actually, many subjects with detectable peanut sIgE antibodies in their serum and/or positive skin test response to peanut do not exhibit clinical manifestations when consuming this legume. The divergence between allergic sensitization and clinically overt allergy not only poses significant diagnostic difficulties but also constitutes a fundamental gap in our knowledge and insights about the complex mechanisms of food allergy and tolerance. Clearly, in prospect for future therapy, better understanding of the underlying (molecular) mechanisms is needed. In this project I will investigate whether the clinical phenotype of peanut sensitization and allergy results from altered basophil responses to stimulation with peanut. More specifically, I will look for alterations in basophilic expression and/or function of three families of functionally distinctive inhibitory receptors, i.e. CD300a, CD32B and Siglec-7, 8 and 9. Obtaining more fundamental insights in the basophil response, may disclose diagnostic but also potential therapeutic targets that have already shown promising preclinical results for various mast cell and basophil associated conditions.

Researcher(s)

• Promoter: Ebo Didier
• Co-promoter: Hagendorens Margo
• Co-promoter: Sabato Vito
• Fellow: Van Gasse Athina

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Despite the high efficacy of allergen-specific immunotherapy, little is known about the mechanisms leading to suppression of basophils and mast cells, which are responsible for the allergic reaction. Therefore, we will assess whether CD300a might be involved in succesfull allergen-specific immunotherapy. It is anticipated that immunotherapy might alter the basophilic and mast cell expression of this receptor, thereby rendering these cells less vulnerable for activation. For this purpose we will apply our recently patented flow cytometric technique that allows a triple analysis of phenotype, signal transduction and histamine release on a single cell level.

Researcher(s)

• Promoter: Ebo Didier
• Fellow: Sabato Vito

Research team(s)

Project type(s)

• Research Project