Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Patients who undergo liver transplantation for autoimmune liver disease (ALD) experience high rates of graft failure. The relative roles of recurrent ALD and rejection can be difficult to distinguish with current methods. This study tests the use of T-cell receptor sequencing of liver biopsies, bile, and stool to distinguish between the two processes.
*Methods: Liver transplant recipients with (n=7), and without ALD (n=3) were enrolled. The putative autoreactive T-cell clonal (ARTCC) repertoire was identified by high throughput sequencing of the T-cell receptor beta chain complementarity-determining region (TCRβ CDR3) of T cells in recipient liver explants, while the donor-reactive T-cell repertoire (DRTCC) was identified by sequencing the TCRβ CDR3 of T cells proliferating in mixed lymphocyte reactions involving donor and recipient pre-transplant peripheral blood mononuclear cells. High throughput sequencing of the TCRβ CDR3 was used to identify putative ARTCC and DRTCC in post-transplant “for cause” liver biopsies, blood, bile and stool samples. TCRβ CDR3s that were detected in both the ARTCC and DRTCC pools were classified as “cross-reactive”.
*Results: Nearly half of the mean cumulative frequencies of the top 20 most dominant T-cell clones in post-transplant liver biopsies were mappable to pre-transplant liver or blood samples for both ALD and non-ALD patients. ALD patients had greater mean cumulative frequencies of putative ARTCC than non-ALD patients in liver biopsies classified as showing rejection (p<0.01). The ratio of mean DRTCC to ARTCC clone fractions among the top 20 clones in biopsies was greater in the non-ALD than the ALD group (p<0.05). In post-transplant blood sequenced for 1 ALD patient, ARTCC constituted >70% of the cumulative frequency of the top 50 CD4+ and the top 50 CD8+ T cell clones. Putative ARTCC and DRTCC were detected in stool and bile samples, along with cross-reactive clones, which were dominant in these samples for some patients.
*Conclusions: The data suggest that recurrent ALD, defined by predominant putative ARTCC in post-transplant samples, is the cause of graft dysfunction in many subjects transplanted for ALD despite a pathological diagnosis of rejection, possibly triggered in some cases by allo- and auto- cross-reactive T cell clones. T-cell receptor sequencing deserves further exploration as a means of differentiating autoimmune recurrence from allograft rejection.
To cite this abstract in AMA style:Yang KJ, Martinez M, Shonts B, Parks CA, Obradovic AZ, Savage TM, Spyrou E, Lau S, Colquhoun MI, Rodgers K, Verna E, Coley SM, Yang S, Shen Y, Sykes M. T-cell Receptor Deep Sequencing to Distinguish Autoimmune Recurrence from Allograft Rejection in Liver Transplant Patients with Autoimmune Liver Disease [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/t-cell-receptor-deep-sequencing-to-distinguish-autoimmune-recurrence-from-allograft-rejection-in-liver-transplant-patients-with-autoimmune-liver-disease/. Accessed October 23, 2020.
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