Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by t...Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by the inclusion of an antigen-specific binding region within the synthetic CAR construct.The advantage of cells with programmed specificity has been demonstrated clinically in the field of oncology,and it is clear that such cells have greater accuracy,potency,and reduced off-target therapeutic effects compared with their unmodified counterparts.In contrast to conventional T cells(Tconvs),regulatory T cells(Tregs)play a major role in suppressing immune activation and regulating the host immune response.CAR expression within Tregs has been proposed as a therapy for autoimmune and inflammatory diseases,graft-versus-host disease(GVHD),and organ transplant rejectio n.In the latter,they hold immense potential as mediators of immune tolerance for recipients of allotransplants.However,current research into CAR-Treg engineering is extremely limited,and there is uncertainty regarding optimal design for therapeutic use.This review examines the rationale behind the development of CAR-Tregs,their significance for human transplantation,potential designs,safety considerations,and comparisons of CAR-Tregs in transplantation models to date.展开更多
Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomic...Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes,guiding new personalised treatments.Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape,cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus(HBV)and HDV or HIV co-infection.Method The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded(FFPE)biopsies from three treatment-naive patients with chronic HBV and HDV or HIV co-infection.The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest(ROIs).Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas.A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Results Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses.Shared features including‘cytotoxicity’and‘B cell receptor signalling’were consistent across patients,suggesting common elements alongside individual traits.HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment,whereas HIV/HBV co-infection featured genes related to interferon response regulation.Varied cellular characteristics and immune cell populations,with an abundance ofγδT cells in the HDV/HBV sample,were observed within analysed regions.Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.Conclusion This proof-of-principle study shows the value of this platform in investigating the complex immune landscape,highlighting relevant host pathways to disease pathogenesis.展开更多
基金supported by the European Union’s Horizon 2020 Research and Innovation Program(RESHAPE,825392)to Joanna Hester and Fadi Issasupported by the Restore Research Trust。
文摘Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by the inclusion of an antigen-specific binding region within the synthetic CAR construct.The advantage of cells with programmed specificity has been demonstrated clinically in the field of oncology,and it is clear that such cells have greater accuracy,potency,and reduced off-target therapeutic effects compared with their unmodified counterparts.In contrast to conventional T cells(Tconvs),regulatory T cells(Tregs)play a major role in suppressing immune activation and regulating the host immune response.CAR expression within Tregs has been proposed as a therapy for autoimmune and inflammatory diseases,graft-versus-host disease(GVHD),and organ transplant rejectio n.In the latter,they hold immense potential as mediators of immune tolerance for recipients of allotransplants.However,current research into CAR-Treg engineering is extremely limited,and there is uncertainty regarding optimal design for therapeutic use.This review examines the rationale behind the development of CAR-Tregs,their significance for human transplantation,potential designs,safety considerations,and comparisons of CAR-Tregs in transplantation models to date.
基金supported by the US Department of Health and Human Services,National Institute of Health/National Institute of Allergy and Infectious Diseases/award(R01AI55182)to DPan Academy of Medical Sciences Starter Grant(SGL021/1030)+3 种基金Seedcorn funding Rosetrees/Stoneygate Trust(A2903)and Mid-Career Research Award from The Medical Research Foundation(MRF-044-0004-F-GILL-C0823)to USGMedical Sciences Division(0011187)Pump-Priming grant awarded to FI and JAMcKResearch in the McKeating laboratory is funded by a Wellcome Investigator Award 200838/Z/16/Z,Wellcome Discovery Award 225198/Z/22/ZChinese Academy of Medical Sciences Innovation Fund for Medical Science,China(grant number:2018-I2M-2-002).
文摘Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes,guiding new personalised treatments.Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape,cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus(HBV)and HDV or HIV co-infection.Method The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded(FFPE)biopsies from three treatment-naive patients with chronic HBV and HDV or HIV co-infection.The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest(ROIs).Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas.A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Results Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses.Shared features including‘cytotoxicity’and‘B cell receptor signalling’were consistent across patients,suggesting common elements alongside individual traits.HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment,whereas HIV/HBV co-infection featured genes related to interferon response regulation.Varied cellular characteristics and immune cell populations,with an abundance ofγδT cells in the HDV/HBV sample,were observed within analysed regions.Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.Conclusion This proof-of-principle study shows the value of this platform in investigating the complex immune landscape,highlighting relevant host pathways to disease pathogenesis.
