Browsing by Author "Marselli, Lorella"

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    First World Consensus Conference on pancreas transplantation: Part II - recommendations
    (Wiley, 2021) Boggi, Ugo; Vistoli, Fabio; Andres, Axel; Arbogast, Helmut P.; Badet, Lionel; Baronti, Walter; Bartlett, Stephen T.; Benedetti, Enrico; Branchereau, Julien; Burke, George W., III; Buron, Fanny; Caldara, Rossana; Cardillo, Massimo; Casanova, Daniel; Cipriani, Federica; Cooper, Matthew; Cupisti, Adamasco; Davide, Josè; Drachenberg, Cinthia; de Koning, Eelco J. P.; Ettorre, Giuseppe Maria; Fernandez Cruz, Laureano; Fridell, Jonathan A.; Friend, Peter J.; Furian, Lucrezia; Gaber, Osama A.; Gruessner, Angelika C.; Gruessner, Rainer W. G.; Gunton, Jenny E.; Han, Duck-Jong; Iacopi, Sara; Kauffmann, Emanuele Federico; Kaufman, Dixon; Kenmochi, Takashi; Khambalia, Hussein A.; Lai, Quirino; Langer, Robert M.; Maffi, Paola; Marselli, Lorella; Menichetti, Francesco; Miccoli, Mario; Mittal, Shruti; Morelon, Emmanuel; Napoli, Niccolò; Neri, Flavia; Oberholzer, Jose; Odorico, Jon S.; Öllinger, Robert; Oniscu, Gabriel; Orlando, Giuseppe; Ortenzi, Monica; Perosa, Marcelo; Perrone, Vittorio Grazio; Pleass, Henry; Redfield, Robert R.; Ricci, Claudio; Rigotti, Paolo; Robertson, R. Paul; Ross, Lainie F.; Rossi, Massimo; Saudek, Frantisek; Scalea, Joseph R.; Schenker, Peter; Secchi, Antonio; Socci, Carlo; Sousa Silva, Donzilia; Squifflet, Jean Paul; Stock, Peter G.; Stratta, Robert J.; Terrenzio, Chiara; Uva, Pablo; Watson, Christopher J. E.; White, Steven A.; Marchetti, Piero; Kandaswamy, Raja; Berney, Thierry; Surgery, School of Medicine
    The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246.
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    IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells
    (Springer, 2018-04) de Brachène, Alexandra Coomans; Dos Santos, Reinaldo Sousa; Marroqui, Laura; Colli, Maikel L.; Marselli, Lorella; Mirmira, Raghavendra G.; Marchetti, Piero; Eizirik, Decio L.; Pediatrics, School of Medicine
    Aims/hypothesis IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition. Methods IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot. Results IFN-α-induced expression of inflammatory and ER stress markers returned to baseline after 24–48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-α, prevented MHC class I overexpression, but when added 24 h after IFN-α exposure these inhibitors failed to accelerate MHC class I return to baseline. Conclusions/interpretation IFN-α mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-α-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-α inhibitors might need to be used at very early stages of the disease to be effective.
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    Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice
    (bioRxiv, 2024-05-09) Syed, Farooq; Ballew, Olivia; Lee, Chih-Chun; Rana, Jyoti; Krishnan, Preethi; Castela, Angela; Weaver, Staci A.; Chalasani, Namratha Shivani; Thomaidou, Sofia F.; Demine, Stephane; Chang, Garrick; de Brachène, Alexandra Coomans; Alvelos, Maria Ines; Marselli, Lorella; Orr, Kara; Felton, Jamie L.; Liu, Jing; Marchetti, Piero; Zaldumbide, Arnaud; Scheuner, Donalyn; Eizirik, Decio L.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treated in vitro with IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP mice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.
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    Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta-cell protection in type 1 diabetes
    (Wiley, 2020-10) Coomans de Brachène, Alexandra; Castela, Angela; Op de Beeck, Anne; Mirmira, Raghavendra G.; Marselli, Lorella; Marchetti, Piero; Masse, Craig; Miao, Wenyan; Leit, Silvana; Evans-Molina, Carmella; Eizirik, Decio L.; Medicine, School of Medicine
    Aim: Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL-1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and methods: Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin-producing EndoC-βH1 cells and human islets to evaluate their effect on IFNα signalling, beta-cell function and susceptibility to viral infection using RT-qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results: The two TYK2 inhibitors tested prevented IFNα-induced human beta-cell gene expression in a dose-dependent manner. They also protected human islets against IFNα + IL-1β-induced apoptosis. Importantly, these inhibitors did not modify beta-cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions: The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro-inflammatory and pro-apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes.