Tosco, Antonella (2016) Transglutaminase 2 in pediatric diseases: pathogenetic, diagnostic and potential role as a target for new therapies. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Transglutaminase 2 in pediatric diseases: pathogenetic, diagnostic and potential role as a target for new therapies.
Autori:
AutoreEmail
Tosco, Antonellaantonella.tosco@unina.it
Data: 29 Marzo 2016
Numero di pagine: 197
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Scienze Mediche Traslazionali
Scuola di dottorato: Medicina clinica e sperimentale
Dottorato: Riproduzione, sviluppo ed accrescimento dell'uomo
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Pignata, Claudiopignata@unina.it
Tutor:
nomeemail
Raia, Valeria[non definito]
Data: 29 Marzo 2016
Numero di pagine: 197
Parole chiave: Transglutaminase2, Cystic Fibrosis, Potential Celiac Disease
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/38 - Pediatria generale e specialistica
Depositato il: 13 Apr 2016 07:35
Ultima modifica: 17 Nov 2016 11:15
URI: http://www.fedoa.unina.it/id/eprint/10801

Abstract

Tissue transglutaminase (TG2) is a ubiquitously expressed member of the transglutaminase family of Ca2+-dependent cross-linking enzymes. It is well known that TG2 is involved in different human diseases. Two of these are typical of childhood such as Celiac Disease (CD) and Cystic Fibrosis (CF). In CD extracellular-TG2 is involved as the target of autoantibodies but also its enzymatic properties play an important role in creating immunogenic, deamidated epitopes of gluten. Starting from the evaluation of the natural history of individuals with no clinical symptoms, production of high titers of serum anti-TG2 antibodies associated to slight or absent mucosal damage, the so-called potential celiac patients, we searched for tools to recognize those who could benefit from gluten free diet (GFD) and we focused our attention to intestinal production of anti TG2 antibodies. We showed, for the first time, that in active CD there was a correlation between levels of intestinal anti-TG2 antibodies and severity of mucosal damage and we found a higher sensitivity and specificity of the dosage of anti-TG2 into culture supernatant compared to anti-TG2 intestinal deposits to detect intestinal production of anti-TG2 antibodies in potential CD patients. We also investigated intestinal production of anti-TG2 even in CD patients on GFD for at least two years showing that in some patients a low amount of anti-TG2 antibodies was secreted but not accumulated as mucosal deposits probably for their low titers and the decreasing affinity of anti-TG2 antibodies for their antigen as a consequence of a long period of GFD. In conclusion the production of intestinal anti-TG2 antibodies could represent the very early stage of the gluten-induced mucosal injury when the integrity of small intestinal mucosa is still conserved and anti-TG2 are not detectable in serum. This test is of potential great impact in clinical practice to unravel the wide spectrum of gluten sensitivity. In CF model we studied the over-expressed intracellular TG2 role in the deranged proteostatic network of cells, and with our model of translational medicine we provide evidence that using a combination of cysteamine and EGCG could be an etiological rather than symptomatic therapy of CF patients bearing at least one allele of Class II CFTR mutation (such as F508del). This is supported by preclinical and clinical evidence. Our results strongly support the idea that the combination of cysteamine and EGCG acts “on-target”. The findings encourage the perspective of “personalizing” CF therapies by means of a translational research approach in which freshly brushed nasal epithelial cells are exposed to candidate drugs and then tested for CFTR function. Thus far, we observed a very good correlation between the capacity of cysteamine and EGCG to improve the function of CFTR in vitro on cultured cells and in vivo, as determined by the sweat test or the functional exploration of freshly recovered nasal epithelia cells. Our novel, safe therapy composed by cysteamine (which is FDA approved for the treatment of cystinosis) and the over-the-counter green tea flavonoid EGCG, is highly affordable (with a>10 times reduction of cost compared to current CFTR-targeted agents in clinical development) and will likely set the bar for future clinical trials based on etiological CF therapy aiming at the repair of the deficient CFTR function. Further large-scale trials assessing the long-term effects of the combination therapy, especially with respect to pulmonary function, nutritional status, subjective well being, as well as the overall cost of patient management, will be required to establish the potential utility of this approach.

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