Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients

Authors

  • Josh Levitsky,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
    2. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
    • M. D., M. S., Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, 19th Floor, Chicago, IL 60611
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    • fax: 312-695-0036

  • James M. Mathew,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
    2. Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Michael Abecassis,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Anat Tambur,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Joseph Leventhal,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Dhivya Chandrasekaran,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Nancy Herrera,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Patrice Al-Saden,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Lorenzo Gallon,

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Anmaar Abdul-Nabi,

    1. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Guang-Yu Yang,

    1. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Sunil M. Kurian,

    1. The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
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  • Daniel R. Salomon,

    1. The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
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  • Joshua Miller

    1. Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL
    2. Jesse Brown VA Medical Center, Chicago, IL
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  • Potential conflict of interest: Nothing to report.

Abstract

Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ∼20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4+CD25+++FOXP3+) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3+/4+); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post–liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3+ cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. Conclusions: TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal. (HEPATOLOGY 2013)

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