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A single cell analysis of allograft rejection and tolerance using mouse solid organ transplantation models

ABSTRACT: Solid organ transplantation in the mouse is a powerful research tool that has provided a pathway to find important mechanistic insights into the regulation of allograft injury, allograft immunopathology, and transplant rejection/tolerance, and that has unique advantages over transplantation in larger species, due to the well characterization of mouse genome and availability of genetically modified animals. However, setup of mouse liver, heart and kidney transplantation is a technically demanding surgical procedure, especially the orthotopic liver transplantation in mouse. Here, we performed Microwell-based single cell RNA-seq of three mouse organ transplantation models (liver, heart and kidney). Comparison of lymphocytes, parenchyma cells and peripheral blood mononuclear cells in liver, heart and kidney revealed distinct immune microenvironment at acute rejection and tolerance state respectively. Single-cell transcriptome analysis of mouse allograft without immunosuppressive drugs provided rich resources to help understand functioning solid-organ transplantation in human.

ORGANISM(S): Mus musculus

PROVIDER: GSE189069 | GEO | 2022/11/18

REPOSITORIES: GEO

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Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models

Project description:Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4+T-bet+ T cells, CD8+T-bet+ T cells, and CD4+FOXP3+ regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2- macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation.

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Protein phosphatase 2A activation promotes heart transplant acceptance in mice

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A single cell analysis of allograft rejection and tolerance using mouse solid organ transplantation models

Project description:A single cell analysis of allograft rejection and tolerance using mouse solid organ transplantation models

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Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance

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2014-10-21 | E-GEOD-52164 | biostudies-arrayexpress

Identification of microRNAs involved in acute rejection and spontaneous tolerance in murine hepatic allografts

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2018-05-07 | E-GEOD-106675 | biostudies-arrayexpress

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Illumina)

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2008-06-15 | E-GEOD-7424 | biostudies-arrayexpress

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