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Frigo, Giulia (2013) Indagine sui meccanismi molecolari alla base dell'efficacia terapeutica delle immunoglobuline G umane. Studi su HUVECs (Human Umbilical Vein Endothelial Cells) e su PBMCs (Peripheral Blood Mononuclear cells). [Ph.D. thesis]

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Abstract (english)

Human Immunoglobulins G (IgG) are increasingly used with beneficial effects in the treatment of a variety of immunological disorders. However, despite the wide therapeutic application, the molecular mechanism by which IgG display their effects is not yet fully elucidated. Several, mutually non-exclusive mechanisms have been proposed that for most part regard effects on cells of immunity, their secretion products and specific IgG receptors. Since IgG are administered by intra venous route and circulate in plasma, the possibility was investigated in this work that IgG can exert their effects on endothelial cells. To this aim, HUVECs (human umbilical vein endothelial cells) that show properties of cells of the innate immunity were chosen in the experimental design and effects of various concentrations of human IgG, purified from blood of healthy donors, measured on cell morphology and on the expression of a panel of heat shock proteins (HSPs) and of matrix metalloprotease-9 (MMP-9) at different incubation times. IgG caused a dose- and time-dependent angiogenic-like transformation of HUVECs that peaked at 20 h incubation and appeared to be associated with the expression of new forms of HSP90, HSP70 and MMP-9 induced by the activation of the PI3K/Akt pathway, whereas the MEK-ERK1/2 pathways was apparently not involved. Measurement of the expression and activity of the proteins in the cell medium demonstrated the active secretion of a proteolytically inactive form of MMP-9 that was secreted in complexes with the HSPs and was responsible for the induction of morphological changes in HUVECs, provided that the stimulus triggered by IgG was sufficiently intense and prolonged. Measurements of IgG expression in both cell lysates and media performed by means of Western blotting and ELISA, together with the analysis of the gene expression of IgG showed that IgG were able to induce their own expression and secretion from the cell. The “ex-novo” synthesis of IgG was triggered by IgG even after they were removed from the incubation medium and replaced with fresh medium without IgG. The process involved the new synthesis of FcRn receptor that was also secreted in association with IgG, a result that proved the participation of FcRn in the cycle of absorbance and secretion of IgG. That the effects of IgG were dependent on their internalization in the cell was also confirmed by immunofluorescence experiments in which IgG were always visualized in the cytoplasm in endocytic vesicles distinct from the cell membrane.
The same experiments performed in HUVECs were also conducted on peripheral blood mononuclear cells of three healthy subjects. IgG caused changes in the lymphocyte morphology associated with the stimulation of both the synthesis and the active secretion of IgG; these effects were crucially dependent in their entity on the basal condition of the immune system of each subject.
Results revealed for the first time the capacity of IgG to induce their own synthesis and secretion in a particular type of endothelial cells physiologically not deputed to these functions. This effect, together with the activation of the immune cells, might be of therapeutic value, since it can enhance and prolong the immune response following the intra venous administration of IgG. The mechanism involved in the "€œex-novo"€ synthesis of IgG appears to be independent of that responsible for the morphological changes of cells that instead requires a more intense and prolonged activating stimulus by IgG.

Abstract (italian)

Le immunoglobuline G (IgG) umane sono sempre più frequentemente usate nella terapia di un’ampia varietà di malattie di natura immunitaria. Nonostante il loro largo impiego, non si conosce ancora il preciso meccanismo molecolare alla base degli effetti benefici riscontrati in queste patologie e le numerose ipotesi formulate riguardano prevalentemente gli effetti esplicati sulle cellule dell’immunità e i loro prodotti di secrezione o su recettori specifici delle IgG.
Dal momento che le IgG terapeutiche vengono somministrate per via endovenosa, in questo lavoro si è voluto verificare l’ipotesi che le IgG potessero esplicare degli effetti sulle cellule endoteliali vascolari con le quali sono costantemente a contatto. Allo scopo, sono state utilizzate cellule endoteliali di cordone ombelicale umano (HUVECs) che mantengono le caratteristiche delle cellule dell’immunità nativa, su cui sono stati testati gli effetti di concentrazioni scalari di IgG (0.1, 0.5 e 1.0 mg/ml) purificate da plasma umano di soggetti sani, valutando le modificazioni morfologiche e misurando l’espressione di Heat Shock Proteins (HSPs) e della metallo proteasi-9 (MMP-9) a tempi e con modalità di incubazione diversi. I risultati hanno dimostrato che le IgG provocano delle significative modificazioni nel fenotipo cellulare compatibili con una trasformazione simil-angiogenetica dipendente dalla concentrazione delle IgG e dal tempo di incubazione, l’effetto massimo essendo visibile dopo 20 h già con 0.5 mg/ml di IgG. Alla base di questo effetto è stata riconosciuta un’intensa stimolazione dell’espressione di nuove forme di HSP90, HSP70 e di MMP-9 a sua volta dipendente dall’attivazione della via metabolica cellulare PI3K/Akt, mentre non risultava coinvolta la via MEK-ERK1/2. La misurazione dell’espressione e dell’attività delle proteine nei terreni di coltura identificava come responsabile della trasformazione morfologica delle HUVECs una forma proteoliticamente inattiva della MMP-9 in complesso con HSP90 e HSP70 , a condizione comunque che lo stimolo delle IgG fosse prolungato nel tempo. La misurazione dell’espressione delle IgG nei lisati cellulari e nei terreni mediante tecniche di Western blotting ed ELISA, assieme all’analisi dell’espressione genica delle IgG dopo trattamento condotto con modalità diverse di incubazione con IgG, evidenziava la capacità delle IgG di stimolare la loro stessa espressione e secrezione. La sintesi “ex-novo” di IgG comunque era un processo che innescato dal contatto relativamente breve con le IgG si manteneva nel tempo anche dopo l’allontanamento dello stimolo. Nel fenomeno era coinvolto attivamente anche il recettore FcRn la cui espressione era indotta solo nelle cellule trattate con IgG e risultava anche secreto assieme alle IgG a riprova del suo coinvolgimento non solo nel processo di assorbimento ma anche di secrezione delle IgG indotte ex-novo. Gli esperimenti di immunofluorescenza indirettamente confermavano come gli effetti sulle HUVECs fossero dipendenti dalla internalizzazione, recettore-mediata delle IgG evidenziate in numerose vescicole endocitiche a localizzazione citoplasmatica.
Esperimenti analoghi condotti in parallelo su cellule mononucleate del sangue periferico di tre soggetti sani, dimostravano la capacità delle IgG di indurre modificazioni morfologiche a carico dei linfociti associate alla stimolazione della produzione ed escrezione di nuove IgG, effetti dipendenti nella loro entità dalle caratteristiche basali del sistema immunitario dei singoli soggetti.
I risultati ottenuti hanno rivelato che le IgG sono in grado di indurre la sintesi e secrezione di nuove IgG da cellule fisiologicamente non deputate a tale funzione come le cellule endoteliali. Questo nuovo effetto delle IgG, mai descritto in precedenza, può essere utile da un punto di vista terapeutico in quanto, in aggiunta alla stimolazione indotta sulle cellule dell’immunità , può potenziare e prolungare nel tempo la risposta immunitaria legata alla somministrazione endovenosa delle IgG. Il meccanismo di sintesi “ex-novo” delle IgG nelle cellule endoteliali appare indipendente da quello responsabile dell’effetto di trasformazione morfologica che è invece un evento che richiede l’applicazione di uno stimolo più intenso e prolungato da parte delle IgG.

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EPrint type:Ph.D. thesis
Tutor:Finotti, Paola
Data di deposito della tesi:30 July 2013
Anno di Pubblicazione:30 July 2013
Key Words:Immunoglobulina G, HUVECs, PBMCs, IVIg
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:6172
Depositato il:27 Mar 2014 12:20
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