Deletion of donor-reactive T cell clones after human liver transplant

Abstract

| INTRODUC TI ONLiver transplantation has been associated with relatively high rates of successful immunosuppression withdrawal in recipients who have been free of rejection for years. 1,2 Despite T cell infiltration associated with hepatitis C virus (HCV) and recurrent HCV posttransplant, 3 a subset of HCV-infected liver transplant recipients have successfully achieved tolerance. 4Spontaneous liver allograft tolerance occurs in rodent models across major histocompatibility complex barriers 5 and is associated with donor-specific tolerance to subsequent skin 6 or cardiac allografts. 7 Moreover, cotransplantation of liver allografts in humans We recently developed a high throughput T cell receptor β chain (TCRβ) sequencing-based approach to identifying and tracking donor-reactive T cells. To address the role of clonal deletion in liver allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was attempted within 2 years of liver transplantation. We identified donor-reactive T cell clones via TCRβ sequencing following a pre-transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non-tolerant subjects. All subjects showed a downward trend and significant reductions in donor-reactive TCRβ sequences were detected post-transplant in 6 of 8 subjects, including 2 tolerant and 4 non-tolerant recipients. Reductions in donor-reactive TCRβ sequences were greater than those of all other TCRβ sequences, including 3rd party-reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Although limited by patient number and heterogeneity, our results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ-and/or protocol-specific nature of tolerance mechanisms in humans. K E Y W O R D Sbasic (laboratory) research/science, immunobiology, liver transplantation/hepatology, monitoring: immune, T cell biology, tolerance

Induction Phase of Spontaneous Liver Transplant Tolerance

“…suggesting that T cell deletion is the most important mechanism mediating tolerance after mouse liver transplantation. It is also consistent with reports suggesting that both the hepatic parenchyma and PLs contribute to tolerance induction after rat LT (18) and that human liver transplantation is associated with deletion of T cells bearing specific TCR beta sequences (60). Tolerance to liver allografts is consistent with our studies showing that persisting high levels of intrahepatic antigen expression, a situation akin to that associated with organ transplantation, are generally associated with tolerance (29).…”

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

“…This would be in keeping with the lack of clinically apparent nonspecific immunosuppressive effects observed following Treg infusion. Alternatively, the infused Tregs could have amplified the well‐documented capacity of liver allografts to delete donor‐reactive T cell clones …”

“…Alternatively, the infused Tregs could have amplified the well-documented capacity of liver allografts to delete donor-reactive T cell clones. 34,35 In summary, we have described here the successful expansion under GMP conditions of polyclonal Tregs isolated from both endstage liver disease patients awaiting liver transplantation and stable liver transplant recipients under maintenance immunosuppression.…”

Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

“…The Colombia group developed a TCR sequencing-based analysis of responding T cells in CFSE-MLR to identify and track a significant fraction of alloreactive T cell repertoire in any donor-recipient pair (105,106). They have shown that liver-induced clonal deletion detected by tracking alloreactive TCR clones in pre-transplant MLR may contribute to achieving tolerance in LT recipients (107). Furthermore, another potentially beneficial application of MLR is the detection of activating induced markers and cytokines.…”