Background: Despite the skin being considered the most immunogenic of all human tissues, full facial transplantation (FFT) has become a life transforming procedure with encouraging results. The purpose of this study was to characterize the immune response upon FFT and identify potential biomarkers of rejection. Unique characteristics in FFT were compared to those of kidney transplantation.

Methods: Since 2011, specimens (PBMCs, serum and skin) from FFT recipients (n=5) were collected prospectively in our center pre-tx, 24h, 1-week and months 3,6,12,24,36 post-tx and when rejection was clinically suspected. All patients received thymoglobulin for induction therapy followed by tacrolimus, MMF, +/-prednisone for maintenance. Prednisone was withdrawn in all patients by 6mo post-tx except one who was highly sensitized. Systemic immune response was characterized by: immunephenotyping of PBMCs by flow cytometry with 32 different markers; functional in vitro ELISPOT assay with irradiated donor PBMC(direct) or lysate donor PBMC(indirect); measurement of 25 relevant cytokines by luminex; anti-HLA, anti-MICA and C1q assays by luminex at all time points.

Results: A total of 45 time-points were analyzed for a mean follow-up of 3.2 years. All patients developed at least one episode of acute cellular rejection during follow-up period. Acute rejections were characterized by an increase in both CD4+ and CD8+ effector T cells (CCR7-CD45RA+; 78.1±18.4% and 68.7±10.6) compared to pre-rejection time-points (19.3±7.6% and 33.8 ±14.4; p<0.05). The percentage of circulating Th17 cells (CD4+CXCR3-CCR6+) was 4-fold higher during acute rejections (p=0.009). Among serum cytokines, MCP-1 levels peaked during rejection (1027±169 vs. 392.5±34 pg/ml prior to rejection; p=0.01). Despite steroid withdrawal, alloimmunogenicity of the skin, and a rise in B cells and Tfh cells overtime (11-fold and 4-fold), we did not observe de novo DSA post-tx. One patient with 3 pre-tx DSAs C1q+ and +CDCXM had complete disappearance of all circulating DSAs by 6mo post-tx. Of note, Tregs(CD4+Foxp3+) had expanded 2-fold by 1-year post-tx, a significant difference compared to a thymo-induced kidney transplant cohort at similar time-point (n=35, p<0.0001).

Conclusions: FFT is frequently complicated by acute cellular rejection, though 3-year outcomes are promising with no evidence of DSA and unique expansion of Tregs.

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