Background: Optimizing immunosuppression requires selecting an agent which can inhibit the dominant anti-rejection mechanism in individual children with liver transplantation (LTx). Extended use of steroids, which are usually eliminated by intent, but used for non-specific suppression may identify those rejection-prone children in whom alternative immunosuppressants may be beneficial. Purpose: To characterize the spectrum of anti-rejection mechanisms in pediatric LTx recipients requiring prednisone maintenance therapy twelve months after LTx. Methods: Whole transcriptome next-generation sequencing (Illumina) was conducted in pre-LTx blood samples from 23 children who received LTx. Differentially expressed genes were identified in 11 children who experienced biopsy-proven acute cellular rejection during the first 60 days after LTx and five children who continued to receive maintenance steroids 12 months after LTx. Drug-gene interaction databases were queried to identify drugs which targeted unique differentially expressed genes (q-value <0.05, fold-change cutoff 1.5-fold) among children requiring steroids. Results: The 263 genes, which were differentially expressed in rejectors, compared with non-rejectors were enriched for the top-ranked canonical pathways which signaled via the T-cell receptor, ICOS-ICOSL, CD28, calcium mediated apoptosis, CTLA4, etc (p=1.83E-14 to 5.18E-09). The 141 genes which were differentially expressed in children receiving steroid, compared with those who were steroid-free (q-value <0.05) included 36 genes which were also differentially expressed among rejectors. The remaining 105 genes were unique to the steroid group and were enriched for the pyrimidine salvage pathway and EIF4/p70S6kinase signaling which is activated by mTOR signaling. Drug-gene interaction databases identified 89 drugs which are known to interact with 16 of 105 genes. Notable drugs included corticosteroids (target ANXA1 or annexin A2), bortezomib (target PSMA4 or prosome, macropain, subunit, alpha type, 4) and SB1578 (target FLT3 or fms-related tyrosine kinase 3), a novel JAK2 inhibitor currently in rheumatoid arthritis trials. Conclusions: Pre-transplant molecular phenotyping can permit selection of immunosuppressants which target dominant anti-rejection mechanisms, potentially optimizing the benefit: risk ratio in each child. Extensive prospective validation is needed.

CITATION INFORMATION: Ningappa M, Ashokkumar C, Sun Q, Higgs B, Soltys K, Bond G, Mazariegos G, Sindhi R. Personalizing Immunosuppression with Molecular Phenotyping in Pediatric Liver Transplantation. Am J Transplant. 2017;17 (suppl 3).

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