*Purpose: Ischemia-reperfusion injury (IRI) is a major risk factor for allograft rejection in orthotopic liver transplantation (OLT), involving complex interactions between innate and adaptive immune systems. However, no clinical therapeutics or patient-specific diagnostics are currently available. Etiologies leading to OLT are heterogeneous, and only ~50% of OLT recipients experience IRI despite similar immunosuppression regimens. Genetic susceptibility to IRI is unknown, and rates of progression differ markedly, as do post-transplant liver function and patient and allograft outcomes. Therefore, we sought to identify associations between inflammatory endotypes and clinical presentations in OLT-IRI.

*Methods: We enrolled 164 OLT recipients in our IRB-approved study. We investigated evolving patient immune status via longitudinal single-antigen bead HLA antibody assay, histopathology and RNAseq of pre- and post-reperfusion biopsies, soluble cytokines, chemokines and growth factors via 38-plex Luminex, and immune cell functional phenotypes via 14-color flow cytometry, PRR activation screening and ELISA. We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features.

*Results: Our studies suggest four clinically actionable human endotypes associated with biopsy-proven IRI centered on the involvement of specific DAMP-PRR signaling pathways: 1) disulfide-HMGB1/TLR4/TNFa, 2) cfDNA/HMGB1/RAGE/TLR9, 3) ssRNA/TLR7 and 4) PGN/NOD2. High-risk IRI endotypes 1 and 2 are associated with increased myeloid activation/infiltration, circulating IL-2, IL-3, IL-4, IL-7, IL-13, IL-1a, IL-17A, IL-1RA, CCL11 and de novo HLA donor-specific antibodies, as well as poorer outcomes, including ACR, AMR and death. Low-risk IRI endotypes 3 and 4 are associated with increased tolerance induction in myeloid and T cells leading to improved outcomes and extended allograft/patient survival. Importantly, we identified female Hispanics with NASH as primarily having high-risk IRI endotype 1. Additionally, high-risk IRI endotype 2 is seen in patients with non-active hepatocellular carcinoma (HCC) at the time of transplant, whereas those with active HCC frequently have low-risk IRI endotypes 3/4.

*Conclusions: Clinical presentations are directly associated with inflammatory endotypes in OLT-IRI. Accurate endotyping of patients according to their specific pathogenesis will allow more precise and personalized therapeutic strategies to reduce the influence of IRI on OLT outcomes.

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