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

ABSTRACT: 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.

SUBMITTER: Abboud R

PROVIDER: S-EPMC10511772 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Abboud Ramzi R Kim Sena S Staser Karl K Jayasinghe Reyka G RG Lim Sora S Amatya Parmeshwar P Frye C Corbin CC Kopecky Benjamin B Ritchey Julie J Gao Feng F Lavine Kory K Kreisel Daniel D DiPersio John F JF Choi Jaebok J

Frontiers in immunology 20230906

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 fu ...[more]

PMID: 37744381

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Project description:BackgroundCardiovascular magnetic resonance (CMR) is emerging as an important tool for cardiac allograft assessment. Native T1 mapping may add value in identifying rejection and in assessing graft dysfunction and myocardial fibrosis burden. We hypothesized that CMR native T1 values and features of textural analysis of T1 maps would identify acute rejection, and in a secondary analysis, correlate with markers of graft dysfunction, and with fibrosis percentage from endomyocardial biopsy (EMB).MethodsFifty cases with simultaneous EMB, right heart catheterization, and 1.5 T CMR with breath-held T1 mapping via modified Look-Locker inversion recovery (MOLLI) in 8 short-axis slices and subsequent quantification of mean and peak native T1 values, were performed on 24 pediatric subjects. A single mid-ventricular slice was used for image texture analysis using nine gray-level co-occurrence matrix features. Digital quantification of Masson trichrome stained EMB samples established degree of fibrosis. Markers of graft dysfunction, including serum brain natriuretic peptide levels and hemodynamic measurements from echocardiography, catheterization, and CMR were collated. Subjects were divided into three groups based on degree of rejection: acute rejection requiring new therapy, mild rejection requiring increased ongoing therapy, and no rejection with no change in treatment. Statistical analysis included student's t-test and linear regression.ResultsPeak and mean T1 values were significantly associated with acute rejection, with a monotonic trend observed with increased grade of rejection. Texture analysis demonstrated greater spatial heterogeneity in T1 values, as demonstrated by energy, entropy, and variance, in cases requiring treatment. Interestingly, 2 subjects who required increased therapy despite low grade EMB results had abnormal peak T1 values. Peak T1 values also correlated with increased BNP, right-sided filling pressures, and capillary wedge pressures. There was no difference in histopathological fibrosis percentage among the 3 groups; histopathological fibrosis did not correlate with T1 values or markers of graft dysfunction.ConclusionIn pediatric heart transplant patients, native T1 values identify acute rejection requiring treatment and may identify graft dysfunction. CMR shows promise as an important tool for evaluation of cardiac grafts in children, with T1 imaging outperforming biopsy findings in the assessment of rejection.

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

Publications

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

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