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 6

T cells are the major source of cytotoxic injury in grade 3 rejection.

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T cells are the major source of cytotoxic injury in grade 3 rejection. (...
(A) T cells are a major but not exclusive source of granzyme B. Multiplex immunostaining demonstrated increased expression of granzyme B in grade 3 rejection, but not all granzyme-producing cells were CD3+ T cells (original magnification, ×100). (B–G) Quantitative multiplex immunostaining was carried out to evaluate the relative contributions of T cells versus NK cells to cytotoxic injury in grade 3 rejection. Bars represent individual donors, and error bars represent the mean and SEM of at least 3 separate measurements per donor. (B) There were significantly more T cells than NK cells in skin biopsies of grade 3 rejection. The numbers of CD3+ T cells and CD56+ NK cells per ×200 HPF are shown. (C) The majority of granzyme B was produced by T cells. The numbers of granzyme-positive CD56+ NK cells and CD3+ T cells per ×200 HPF are shown. (D) There were significantly more activated T cells than activated NK cells. The numbers of CD3+CD40L+ (activated T) cells and CD56+CD107a+ (activated NK) cells per ×200 HPF are shown. (E) NK cells had higher frequencies of activation. The percentages of total CD3+ T cells expressing CD40L (left) and CD56+ NK cells expressing CD107a (right) are shown. (F and G) T cells mediated significantly more cytotoxic events than NK cells. Cells undergoing cytotoxic cell death were identified by immunostaining for caspase-8, and the number (F) and relative frequency (G) of events in which T cells (left) or NK cells (right) were juxtaposed with dying cells were enumerated. Significance was determined by nested t tests.