Project description:Background: T-cell mediated rejection (TCMR) remains a significant challenge after kidney transplantation and is associated with reduced allograft outcome. Previous research highlighted the critical role of TCMR-induced renal epithelial injury. Yet, the detailed cellular origin of these injury responses and the associated clinical implications remain poorly understood. Methods: To induce acute TCMR, we used mouse models of allogeneic (C57BL/6 to BALB/c and BALB/c to C57BL/6) kidney transplantation and syngeneic controls (C57BL/6 to C57BL/6 and BALB/c to BALB/c). Molecular changes were analyzed 7 days post-transplant using single-nucleus RNA sequencing and spatial transcriptomics. Results were compared with snRNA-seq data from three human TCMR biopsies and three stable allografts without rejection. The clinical impact of TCMR-induced epithelial injury was evaluated using marker gene sets on bulk transcriptomic data from 1292 kidney allografts, including 95 TCMR samples, with allograft outcome. Results: Mouse kidneys from allogeneic transplants exhibited all hallmark histological features of TCMR. Single-nucleus RNA sequencing revealed TCMR-induced injured cell states and significant gene expression changes particularly in proximal tubules (PT) and thick ascending limbs (TAL). Spatial transcriptomics showed a heterogeneous spatial distribution of these injured cell states and proximity to leukocytes. Cross-species analysis confirmed similar injured PT and TAL cell states in human TCMR. Signatures of a severely injured TCMR-induced TAL cell state correlated strongly with allograft survival in a large kidney transplant cohort specifically after TCMR. Conclusion: This is the first study showing kidney allograft outcome with distinct injured epithelial cell states. We found a particularly strong correlation between kidney allograft survival and TAL injury in TCMR, which occurred with reduced proximity to leukocytes, suggesting potential epithelial injury driven by non-immune mechanisms.

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Autograft and allograft samples from femur

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