Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection
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
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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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 2

Effector T cell molecules, T cell cosignaling, and IFN-γ signaling molecules are upregulated in acute cellular rejection of face transplants.

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Effector T cell molecules, T cell cosignaling, and IFN-γ signaling molec...
(A–J) Volcano plots showing genes differentially expressed in grade 3 rejection biopsies (n = 11) versus grade 0 nonrejection biopsies (n = 10). DEGs were obtained using normalized gene expression counts as input and the Wald significance test. Each dot represents an individual gene. Horizontal dashed lines represent an adjusted P value cutoff of –log10 (0.05); vertical dashed lines represent log2 fold change of –1 and +1. Synonymous gene symbols, according to NCBI Gene, are provided in parentheses. All volcano plots illustrate identical data, but each highlights selected genes associated with leukocyte trafficking (A); T cell infiltration (B); T cell costimulation (C); T cell coinhibition (D); IFN-γ signaling (E); Th1 chemokine receptors and their ligands (F); effector molecules (G); immunoregulation (H); antigen processing and presentation (I); or innate immunity (J). (K) The top 25 canonical pathways overrepresented in 202 DEGs in grade 3 rejection biopsies in relation to grade 0 are shown. The significance of the association between gene expression and canonical pathways was estimated by the P value (depicted in bar graphs; primary y axis), and the ratio value reflects its strength (depicted as line graphs; secondary y axis). P values were determined using Fisher’s exact test with multiple testing adjustments according to the Benjamini-Hochberg false discovery rate method.