A clinical research consortium sponsored by NIAID
Feng S, Ekong U, Lobritto S, Demetris A, Rosenthal P, Alonso E, Philogene M, Ikle D, Phippard D, 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 Federal Systems Division, Chapel Hill, NC Immune Tolerance Network, San Francisco, CA
ABSTRACT
BACKGROUND: ITN029 is a multi-center pilot trial of immunosuppression withdrawal in pediatric recipients of parental living donor liver transplants. We report clinical and histological 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 operationally tolerant, having maintained normal allograft function in the absence of immunosuppression for 25.5-46.0 mos. Tolerant children were farther out from transplant (99.5±30.0 mos 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 moderate positive correlation (Pearson r = 0.752). Donor/recipient demographics, maintenance immunosuppression, rejection history, baseline ALT/GGT, HLA mismatch, presence/absence of donor specific antibody, 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.
