puplications of TWINCORE unit [TC] Adminhttp://hdl.handle.net/10033/6214952024-03-28T13:48:44Z2024-03-28T13:48:44ZGuidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference.Cornberg, MarkusLok, Anna Suk-FongTerrault, Norah AZoulim, Fabienhttp://hdl.handle.net/10033/6232052022-06-14T01:56:56Z2020-03-01T00:00:00ZGuidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference.
Cornberg, Markus; Lok, Anna Suk-Fong; Terrault, Norah A; Zoulim, Fabien
2020-03-01T00:00:00ZEvolution of cytokine production capacity in ancient and modern European populations.Domínguez-Andrés, JorgeKuijpers, YunusBakker, Olivier BJaeger, MartinXu, Cheng-JianVan der Meer, Jos WmJakobsson, MattiasBertranpetit, JaumeJoosten, Leo AbLi, YangNetea, Mihai Ghttp://hdl.handle.net/10033/6230762021-10-21T03:21:07Z2021-09-07T00:00:00ZEvolution of cytokine production capacity in ancient and modern European populations.
Domínguez-Andrés, Jorge; Kuijpers, Yunus; Bakker, Olivier B; Jaeger, Martin; Xu, Cheng-Jian; Van der Meer, Jos Wm; Jakobsson, Mattias; Bertranpetit, Jaume; Joosten, Leo Ab; Li, Yang; Netea, Mihai G
As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.
2021-09-07T00:00:00ZTherapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.Yang, TaihuaPoenisch, MarionKhanal, RajendraHu, QingluanDai, ZhenLi, RuomengSong, GuangqiYuan, QinggongYao, QunyanShen, XizhongTaubert, RichardEngel, BastianJaeckel, ElmarVogel, ArndtFalk, Christine SSchambach, AxelGerovska, DanielaAraúzo-Bravo, Marcos JVondran, Florian W RCantz, TobiasHorscroft, NigelBalakrishnan, AshaChevessier, FrédéricOtt, MichaelSharma, Amar Deephttp://hdl.handle.net/10033/6230712021-10-13T03:22:02Z2021-08-25T00:00:00ZTherapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.
Yang, Taihua; Poenisch, Marion; Khanal, Rajendra; Hu, Qingluan; Dai, Zhen; Li, Ruomeng; Song, Guangqi; Yuan, Qinggong; Yao, Qunyan; Shen, Xizhong; Taubert, Richard; Engel, Bastian; Jaeckel, Elmar; Vogel, Arndt; Falk, Christine S; Schambach, Axel; Gerovska, Daniela; Araúzo-Bravo, Marcos J; Vondran, Florian W R; Cantz, Tobias; Horscroft, Nigel; Balakrishnan, Asha; Chevessier, Frédéric; Ott, Michael; Sharma, Amar Deep
Background & aims: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis.
Methods: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation.
Results: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells.
Conclusion: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.
Lay summary: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.
2021-08-25T00:00:00ZTransient Depletion of Foxp3 Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice.Watts, DeepikaJanßen, MartheJaykar, MangeshPalmucci, FrancescoWeigelt, MarcPetzold, CathleenHommel, AngelaSparwasser, TimBonifacio, EzioKretschmer, Karstenhttp://hdl.handle.net/10033/6230422021-09-27T11:01:38Z2021-08-10T00:00:00ZTransient Depletion of Foxp3 Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice.
Watts, Deepika; Janßen, Marthe; Jaykar, Mangesh; Palmucci, Francesco; Weigelt, Marc; Petzold, Cathleen; Hommel, Angela; Sparwasser, Tim; Bonifacio, Ezio; Kretschmer, Karsten
Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.
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