Proliferative alloresponse of T-cytotoxic cells identifies rejection-prone children with steroid-free liver transplantation

Abstract

Donor-induced and third-party-induced proliferation of T-helper and T-cytotoxic (Tc) cells and their naïve and memory subsets was evaluated simultaneously in single blood samples from 77 children who received steroid-free liver transplantation (LTx) after induction with rabbit anti-human thymocyte globulin. Proliferation was measured by dilution of the intravital dye carboxyfluorescein succinimidyl ester (CFSE) in a 3-to 4-day mixed lymphocyte response coculture. The ratio of donor/third-party-induced proliferated (CFSE low ) T-cells was reported as the immunoreactivity index (IR) for each subset. Rejectors were defined as those who experienced biopsy-proven acute cellular rejection within 60 days of the assay. IR Ͼ 1 signified increased risk of rejection, and IR Ͻ 1 implied decreased risk. Demographics for 32 rejectors and 45 nonrejectors were similar. Proliferated CFSE low T-cells and subsets were significantly higher among rejectors compared with nonrejectors. In 33 of 77 randomly selected children, logistic regression, leave-one-out cross-validation, and receiver operating characteristic analyses showed that the IR of Tc cells was best associated with biopsy-proven rejection (sensitivity Ͼ 75%, specificity Ͼ 88%). Sensitivity and specificity were replicated in the remaining 44 children who composed the validation cohort. IR of CFSE low Tc cells correlated significantly with IR of proinflammatory, allospecific CD154ϩ Tc cells (r ϭ 0.664, P ϭ 0.0005) and inversely with IR of allospecific, anti-inflammatory, cytotoxic T lymphocyte antigen 4 -positive Tc cells (r ϭ Ϫ0.630, P ϭ 0.007).In conclusion, proliferative alloresponses of Tc cells can identify rejection-prone children receiving LTx. Liver Transpl 15: 978-985, 2009.

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

“…Donor-specific T cells responses have been shown to predict the risk of acute rejection following pediatric LT, (60) but they have not been investigated in idiopathic graft hepatitis and fibrosis.…”

Peripheral blood biomarkers for the characterization of alloimmune reactivity after pediatric liver transplantation

“… observed decreased numbers of CD4 + cells in patients with rejection after living‐related liver transplantation. Significantly higher CD8 + T‐cell counts were described in pediatric and adult liver transplant recipients with rejection than in non‐rejectors , and an increasing CD8 + T‐cell proliferation capacity and immune reactivity could correspond to higher T‐cell numbers in peripheral blood . Although rejection is mediated primarily by CD4 + T cells, the role of CD8 + T cells as a major cytotoxic effector lymphocyte population in graft rejection has been well established .…”

Inflammatory markers sampled by microdialysis catheters distinguish rejection from ischemia in liver grafts

“…Most rejections of liver transplants are cellular rather than antibody‐mediated, and T lymphocytes are central players 1. Acute cellular rejection (ACR) typically occurs within the first 6 weeks after transplantation and is a relatively frequent complication with an incidence in the range of 30% to 60% 2.…”