Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation

American Journal of Transplantation, vol. 22, pp. 2529–2547

Abstract

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naïve and transplanted young versus aged kidneys revealed that naïve aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8+ T cells produced more IFNγ than their young counterparts. Senescent renal CD8+ T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a+CXCR6+ NK cells was documented in aged naïve kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFNγ, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFNγ and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft.

Authors 17

1. An He

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

2. Attia Sarwar

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

3. Linda Marie Laura Thole

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

4. Janine Siegle

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

5. Arne Sattler

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

6. Muhammad Ashraf

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

7. Vanessa Proß

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

8. Carolin Stahl

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

9. Theresa Dornieden

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

10. Yasmin Bergmann

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

11. Paul Viktor Ritschl

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany

12. Susanne Ebner

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria

13. Karolin W. Hublitz

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin

    Affiliation as printed

    Institute of Microbiology, Infectious Diseases and Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

    Institute of Microbiology, Infectious Diseases and Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

14. Efstathios G. Stamatiades

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin

    Affiliation as printed

    Institute of Microbiology, Infectious Diseases and Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

    Institute of Microbiology, Infectious Diseases and Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

15. Roman David Bülow Aachen Institute of Pathology Department of Nephrology, University Clinic

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Pathology & Department of Nephrology, University Clinic of RWTH Aachen, Aachen, Germany

16. Peter Boor Aachen Institute of Pathology Department of Nephrology, University Clinic

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Pathology & Department of Nephrology, University Clinic of RWTH Aachen, Aachen, Germany

17. Katja Kotsch corresponding

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Freie Universität Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of General- and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany