Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection
Thet Su Win, … , Leonardo V. Riella, Rachael A. Clark
Thet Su Win, … , Leonardo V. Riella, Rachael A. Clark
Published March 5, 2021
Citation Information: J Clin Invest. 2021;131(8):e135166. https://doi.org/10.1172/JCI135166.
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Clinical Research and Public Health Immunology

Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection

Abstract

BACKGROUND Rejection is the primary barrier to broader implementation of vascularized composite allografts (VCAs), including face and limb transplants. The immunologic pathways activated in face transplant rejection have not been fully characterized.METHODS Using skin biopsies prospectively collected over 9 years from 7 face transplant patients, we studied rejection by gene expression profiling, histology, immunostaining, and T cell receptor sequencing.RESULTS Grade 1 rejection did not differ significantly from nonrejection, suggesting that it does not represent a pathologic state. In grade 2, there was a balanced upregulation of both proinflammatory T cell activation pathways and antiinflammatory checkpoint and immunomodulatory pathways, with a net result of no tissue injury. In grade 3, IFN-γ–driven inflammation, antigen-presenting cell activation, and infiltration of the skin by proliferative T cells bearing markers of antigen-specific activation and cytotoxicity tipped the balance toward tissue injury. Rejection of VCAs and solid organ transplants had both distinct and common features. VCA rejection was uniquely associated with upregulation of immunoregulatory genes, including SOCS1; induction of lipid antigen–presenting CD1 proteins; and infiltration by T cells predicted to recognize CD1b and CD1c.CONCLUSION Our findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.Trial registration ClinicalTrials.gov NCT01281267.FUNDING Assistant Secretary of Defense and Health Affairs, through Reconstructive Transplant Research (W81XWH-17-1-0278, W81XWH-16-1-0647, W81XWH-16-1-0689, W81XWH-18-1-0784, W81XWH-1-810798); American Society of Transplantation’s Transplantation and Immunology Research Network Fellowship Research Grant; Plastic Surgery Foundation Fellowship from the American Society of Plastic Surgeons; Novo Nordisk Foundation (NNF15OC0014092); Lundbeck Foundation; Aage Bangs Foundation; A.P. Moller Foundation for the Advancement of Medical Science; NIH UL1 RR025758.

Authors

Thet Su Win, William J. Crisler, Beatrice Dyring-Andersen, Rachel Lopdrup, Jessica E. Teague, Qian Zhan, Victor Barrera, Shannan Ho Sui, Sotirios Tasigiorgos, Naoka Murakami, Anil Chandraker, Stefan G. Tullius, Bohdan Pomahac, Leonardo V. Riella, Rachael A. Clark

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Figure 1

Human face transplant rejection has a distinct gene expression signature.

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Human face transplant rejection has a distinct gene expression signature...
(A) Design of the study. Skin biopsies from 7 face transplant patients collected during episodes of acute cellular rejection (red) and nonrejection (green) were analyzed using histologic examination, multiplex gene expression profiling, and immunostaining. (B) Clinical photographs of a recipient of a full face transplant during nonrejection (grade 0) and severe acute cellular rejection (grade 3), demonstrating edema and erythema of the transplanted face. (C) Representative examples of H&E staining of a face transplant skin biopsy graded as nonrejection (grade 0, minimal inflammatory infiltrates), and a second biopsy graded as severe acute cellular rejection (grade 3, dermal inflammatory infiltrates with apoptotic keratinocytes). (D) Unsupervised principal component analysis clustered grade 3 rejection biopsies (n = 11) separately from grade 0 samples (n = 10). (E) Heatmap of the top 50 genes differentially expressed in grade 3 compared with grade 0 biopsies (log2 fold change >1; adjusted P value <0.05). Differentially expressed genes (DEGs) were obtained using normalized gene expression counts as input and the Wald significance test. Each column represents a facial allograft biopsy. Gene values are row scaled. The full list of differentially expressed genes and associated statistics are shown in Supplemental Table 3.