A clinical research consortium sponsored by NIAID
Phippard D, Feng S, Ekong U, Lobritto S, Demetris A, Rosenthal P, Alonso E, Ikle D, Philogene M, Tchao N
University of California, San Francisco, San Francisco, CA; Northwestern University, Chicago, IL; Columbia University, New York, NY; University of Pittsburgh, Pittsburgh, PA; Rho, Chapel Hill, NC; Immune Tolerance Network, San Francisco, CA and Bethesda, MD.
BACKGROUND: ITN029 is a multi-center pilot trial of immunosuppression withdrawal in pediatric recipients of parental living donor liver transplants. We aim to identify predictors of operational tolerance.
METHODS: Clinical and histological variables were compared using Fisher's exact test or a t-test with a two-tailed 0.05 alpha level. Formalin-fixed pre-withdrawal biopsies were prospectively scored for 48 pre-specified histopathologic criteria. Snap frozen biopsies were scored for total C4d by summing the score for each vascular compartment and surrounding stroma (portal vein/capillary/stroma, hepatic artery, sinusoid, central vein/stroma).
RESULTS: Among the 19 evaluable participants, 12 are tolerant, maintaining normal allograft function in the absence of immunosuppression for 24.5-45.0 mos. Tolerant children were further out from transplant (99.5±30.0 vs. 69.6±13.7 mos; p=0.025), exhibited less portal inflammation (11/12 vs 3/7 with no inflammation; p=0.038), and had lower C4d score (7.31±3.35 vs 12.39±3.34; p=0.019) in the baseline biopsy than non-tolerant children. Baseline C4d score and donor specific antibody strength showed a moderately positive correlation (Pearson r=0.752). Donor/recipient demographics, maintenance immunosuppression, rejection history, baseline ALT/GGT, HLA mismatch, presence/absence of donor specific antibodies, and other biopsy features such as fibrosis, interface activity, and steatosis were not associated with tolerance.
CONCLUSIONS: ITN029 has identified promising clinical and histological predictors of operational tolerance in a cohort of pediatric liver transplant recipients. Larger studies are necessary to validate these predictors in both children and adults and to determine if they can be combined into a clinically useful model to accurately guide immunosuppression withdrawal.
