Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models
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ABSTRACT:
PROVIDER: PRJNA1123755 | ENA |
REPOSITORIES: ENA
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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.
2024-06-13 | GSE269828 | GEO
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.
| S-EPMC10511772 | biostudies-literature
Project description:To elucidate the gene profile of anti-fibroproliferative effects of cyclosporine, we added TGF-b and/or CsA to MRC5 (fetal human lung fibroblast) cell line. After 24 hours serum starvation, fibroblasts were treated with 3 ng/ml TGF-β1 and were treated with or without 2μg/ml Cyclosporine and effects were examined at 48 hours after treatment. Expression of three genes (IGFBP3, ID1 and PPARG) from this signature was quantified in the same RNA samples by real-time PCR. TGF-β and cyclosporine induced gene expression data was measured in MRC5 (fetal human fibroblast cell line) at 48h after treatments. The dose of TGF-β was 3 ng/ml and cyclosporine was 2 μg/ml. The comparison was done between four groups (control, TGF-β, cyclosporine and TGF-β plus cyclosporine).Three independent experiments were performed at each treatments using different samples for each experiment.
2010-11-09 | E-GEOD-25200 | biostudies-arrayexpress
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in systemic form at the time of grafting. Skin samples were taken after 12 weeks.
2015-05-01 | E-GEOD-61551 | biostudies-arrayexpress
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in systemic form after disease establishment. Skin samples were taken at the start of treatment and after 12 weeks.
2015-05-01 | E-GEOD-61552 | biostudies-arrayexpress
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in topical form after disease establishement. Skin samples were taken at the start of treatment and after 12 weeks.
2015-05-01 | E-GEOD-61554 | biostudies-arrayexpress
Project description:To elucidate the gene profile of anti-fibroproliferative effects of cyclosporine, we added TGF-b and/or CsA to MRC5 (fetal human lung fibroblast) cell line. After 24 hours serum starvation, fibroblasts were treated with 3 ng/ml TGF-β1 and were treated with or without 2μg/ml Cyclosporine and effects were examined at 48 hours after treatment. Expression of three genes (IGFBP3, ID1 and PPARG) from this signature was quantified in the same RNA samples by real-time PCR.
2010-11-09 | GSE25200 | GEO
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models.
2015-05-01 | GSE61554 | GEO
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models.
2015-05-01 | GSE61552 | GEO
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models.
2015-05-01 | GSE61551 | GEO