Biphasic JAK-STAT-IFN Signaling Distinguishes Liver Transplant Rejection from Quiescence, Highlighting JAK Inhibition

Subclinical rejection after liver transplantation is a significant challenge, often precluding successful immunosuppression withdrawal despite normal clinical function. Understanding the underlying immunobiology of this early rejection is crucial to identify predictive biomarkers and novel therapeutic targets. Current standard-of-care immunosuppression aims to prevent rejection but carries long-term side effects, and its withdrawal is often unsuccessful due to these subclinical immune responses. This study investigates the role of Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-interferon (IFN) signaling as a potential key pathway in distinguishing rejection from stable allograft function.

Researchers conducted longitudinal, multimodal immune profiling and single-cell RNA sequencing (scRNA-seq) on 13 adult living-donor liver transplant recipients participating in an immunosuppression withdrawal trial. They compared samples from patients with subclinical rejection ("nonpermissive") at 12 months post-transplant against those with quiescent ("permissive") allografts. The study also leveraged internal and external bulk RNA-seq and scRNA-seq liver transplant cohorts, including a rodent model, to validate findings. Furthermore, phosphorylated STAT1 staining was performed on biopsies, and ruxolitinib-mediated JAK inhibition was tested in vitro to assess its effect on alloreactive CD8+ T cell proliferation and inflammatory mediator production.