Renal inflamm‐aging provokes intra‐graft inflammation following experimental kidney transplantation. Issue 11 (30th July 2022)

• Record Type: Journal Article
• Authors: He, An; Sarwar, Attia; Thole, Linda Marie Laura; Siegle, Janine; Sattler, Arne; Ashraf, Muhammad Imtiaz; Proß, Vanessa; Stahl, Carolin; Dornieden, Theresa; Bergmann, Yasmin; Ritschl, Paul Viktor; Ebner, Susanne; Hublitz, Karolin Wiebke; Stamatiades, Efstathios Gregorios; Bülow, Roman David; Boor, Peter; Kotsch, Katja
• Is Part Of: American journal of transplantation. Volume 22:Issue 11(2022)
• Page Start: 2529
• Page End: 2547
• Publication Date: 2022-07-30
• Subjects: inflamm‐aging -- kidney transplantation -- senescence -- senolytic drug; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.17154
• Languages: English
• ISSNs: 1600-6135

Abstract

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. Abstract : Aging‐associated alterations of kidney‐resident leukocytes, endothelial and epithelial cells exacerbates intra‐graft inflammation after experimental kidney transplantation that can be mitigated by senolytics.