Analyzing the impact of T-cell receptor diversity in acute kidney transplant rejection
Tara Sigdel1, Paul Fields2, Juliane Liberto1, Izabella Damm1, Maggie Kerwin1, Jill Hood2, Parhom Towfighi1, Marina Sirota1, Harlan Robins2, Minnie Sarwal1.
1UCSF, San Francisco, CA, United States; 2Adaptive Biotechnologies, Seattle, WA, United States
Purpose: Recent developments in T-cell receptor (TCR) immunosequencing allow for analysis of alloreactive human T-cell populations both before and after engraftment. In this study, we mapped T-cell repertoire from transplant recipients and assessed the role of chronological changes in T-cell clonality, immune repertoire turnover, T-cell Fraction (TCFr), and tissue pathological score to acute rejection (AR) risk stratification and management.
Methods: The study included 339 blood samples, collected before and after transplantation, from 200 kidney transplant recipients; 100 with biopsy confirmed acute rejection (AR), 100 with biopsy confirmed stable (STA) allograft histology.Immunosequencing of the CDR3 regions of human TCRβ locus was performed using the immunoSEQ Assay. Sequences were collapsed and filtered in order to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region for further analysis.
Results: More diverse T-cell Repertoire at baseline was associated with AR post-transplant. When compared to STA patients, AR patients had lower (TCFr) before transplantation (p=0.01). After transplantation, patients who developed rejection had greater repertoire turnover (p=0.0024) and increased TCFr. Significant increase in T-cell fraction at late rejection and in ABMR was observed which was significant in late rejection cases >6 mo post-transplantation (p<0.001)(Fig1A). There was an increase in T-cell fraction in ABMR compared to non-ABMR samples (p=0.05)(Fig1B). There was an increased peripheral T-cell fraction among AR subjects compared to STA among AR samples collected at 6 mo post-transplantation (p=0.003)(Fig1C). TCFr also correlated with microcirculation inflammation.
Conclusions: In conclusion, our study demonstrated that T-cell repertoire changes with post-transplant rejection episodes and suggested that the T-cell repertoire changes may provide pre-transplant and post-transplant predictors of rejection risk which in turn can support immunosuppression management decisions at and after transplantation.
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