Sentinel flaps correlate with pro-inflammatory and immunoregulatory mediators of human face transplantation rejection

Abstract

Abstract Early diagnosis and treatment of immune rejection is critical for face transplants (vascularized composite allografts, VCA). VCA rejection is diagnosed by histologic evaluation of skin biopsies, yet repeated biopsies are a considerable aesthetic problem. Sentinel flaps, fasciocutaneous radial forearm flaps, have been used for remote-site rejection monitoring, but the concordance between tissues during rejection remains unclear. With access to the world’s largest cohort of VCA patients at a single center worldwide, we studied 14 paired skin biopsies from sentinel flaps (SF) and facial allografts (FA) during rejection and non-rejection. We previously identified 15 pro-inflammatory genes (including GZMB, HLA-DPB1, IFNG) and 15 immunoregulatory genes (including SOCS1, CTLA4, IDO1) upregulated in VCA rejection. SF and FA had an average correlation coefficient of 0.88 and 0.76 for pro- and anti-inflammatory gene sets, respectively. During rejection, there was no significant difference in expression of the 15 pro-inflammatory genes between tissue type (SF versus FA), and only one immunoregulatory gene (PDCD1) was significantly different. Across all samples, there were 64 differentially expressed genes (DEG) between rejection and non-rejection, 13 DEG between tissue types, and only 2 DEG when statistically accounting for differences in tissue type driven by rejection status (log2FC>1, p<0.05). High throughput sequencing (HTS) of the CDR3 of TCR-β genes from 4 matched pairs during rejection identified a mean of 9.5 expanded shared T cell clones, indicating that shared antigens drove rejection in both tissues. Together, these data indicate that SF could serve as effective remote-site monitoring for face transplant rejection. NIH T32 Training Grant 2T32AR007098-47 Dept. of Dermatology, Harvard Medical School RT170025 (P.I. Rachael A. Clark) Department of Defense - congressionally Directed Medical Research Programs; "T cells and Rejection in Vascularized Composite Allografts).