Sentinel flaps reflect key inflammatory aspects of human face transplant rejection

William J Crisler; Thet Su Win; Martin Kauke-Navarro; Qian Zhan; Victor Barrera; Shannan Ho Sui; Alvaro C Laga; Jessica E Teague; Leonardo V Riella; Jamil Azzi; Bohdan Pomahac; Rachael A Clark

doi:10.1016/j.ajt.2025.12.009

Sentinel flaps reflect key inflammatory aspects of human face transplant rejection

Am J Transplant. 2025 Dec 15:S1600-6135(25)03168-5. doi: 10.1016/j.ajt.2025.12.009. Online ahead of print.

Authors

Affiliations

¹ Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: w.crisler@bwh.harvard.edu.
² Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Division of Plastic Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
⁴ Harvard Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
⁷ Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: rclark@bwh.harvard.edu.

PMID: 41407105
DOI: 10.1016/j.ajt.2025.12.009

Abstract

Early diagnosis and treatment of immune rejection is critical for maintaining the viability of face transplants, a type of vascularized composite allograft (VCA). Surveillance currently involves multiple skin biopsies that leave scars. Fasciocutaneous sentinel flaps (SFs) have been proposed as remote-site monitors of rejection, but the molecular immune events in SFs during rejection have never been compared to those in facial allografts (FAs). We used transcriptional profiling, immunostaining, and high-throughput T cell receptor sequencing to study 14 matched skin SF and FA biopsies during rejection and nonrejection. SFs and FAs shared common signatures of rejection, including proinflammatory and immunoregulatory genes we previously identified as key indicators of VCA rejection. SFs and FAs both exhibited antigen-specific T cell activation and T cell granzyme B-mediated cytotoxic injury. High-throughput T cell receptor sequencing of complementarity determining region 3 T cell receptor β genes from 4 matched pairs during rejection revealed shared T cell clones in both tissues, indicating that shared antigens were driving rejection at both sites. Our results suggest that SFs reflect inflammation and clinically significant (grade 2-3) rejection in VCA, with less specificity for distinguishing mild (grade 1) changes from nonrejection.

Keywords: T cell receptor sequencing; cytotoxic T lymphocytes; facial allograft; immune rejection; sentinel flap; vascularized composite allotransplantation.