Grafts of operationally tolerant patients after LDLT did not exhibit acute or chronic rejection, but they exhibited fibrosis. It remains elusive whether fibrosis observed in tolerant grafts is antigen dependent. The finding that after [corrected] the reintroduction or the increase of IS fibrosis was improved supported the possibility that fibrosis in operationally tolerant patients was antigen dependent.
Anti-AT1R Ab and DSA-DRB1 may be candidates as biomarkers of graft fibrosis; both HLA and non-HLA immunity may be involved in graft fibrosis after IS withdrawal.
Summary
Pediatric recipients of living‐donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi‐allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post‐Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr‐tol), but not in 50 intolerant patients (Gr‐intol). The Gr‐intol consisted of 24 patients with rejection (Gr‐rej) and 26 with fibrosis of grafts (Gr‐fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11–7.02, P = 0.03], was a positive independent predictor, whereas HLA‐A mismatch (0.18, 0.03–0.91, P = 0.04) was a negative predictor. HLA‐DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr‐intol (4.9%) compared with Gr‐tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr‐Tol (P = 0.02). Although HLA‐B mismatch (8.73, 1.09–70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA‐A match and the later predominance of Tregs are factors associated with OT.
This is the first report providing detailed evidence that donor-specific naïve-Tregs were generated and their suppressive properties were upregulated in the peripheral blood of tolerant patients, whereas their frequency was downregulated in intolerant patients. Therefore, we speculate that not only conventional-Tregs play a role in Tx tolerance but also the role of naïve-Tregs is critical.
A unique Vδ1-bearing T-cell clone accumulates within accepted human liver grafts. It might be useful as a biomarker of tolerance and the identification of its ligand might aid in the development of a novel strategy for tolerance induction.
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