Th14 - Crosstalk Between Alloimmunity and Ischemia-Reperfusion Injury in Human Liver Transplantation

Recipient sensitization to donor HLA antigens and ischemia-reperfusion injury (IRI) are key challenges in liver transplantation (LT), increasing waitlist times and/or risk of acute and chronic cellular and antibody-mediated rejection. Yet it is still unresolved whether pre-transplant alloreactivity potentiates IRI or if IRI enhances post-transplant alloimmunity. We evaluated donor-specific HLA class I/II antibodies (DSA) pre- and at two timepoints post-transplant (early=within 3 months, late=4 months–2 years) in LT recipients with or without biopsy-proven IRI (n=78; IRI-=37, IRI+=41) using single antigen bead-based HLA antibody testing and intermediate resolution HLA typing. Only 25% of LT recipients pre-sensitized to HLA-DSA experienced IRI, suggesting pre-transplant exposure to HLA can tolerize against IRI. The number of IRI- patients producing allo-antibodies significantly decreased from pre- to early post-transplant, continuing to decrease late post-transplant. Further, only IRI+ patients who were not pre-sensitized had an early memory response that persisted through late testing or produced de novo antibodies late post-transplant, with DSA being higher than in IRI- patients at both timepoints. IRI- patient sensitization was more frequently against class I or I/II whereas IRI+ sensitization was against only class II. Finally, although more females were pre-sensitized, IRI+ recipients experienced increased post-transplant alloimmunity irrespective of gender. Our data reveal that pre-sensitized LT recipients, particularly those with DSA, are protected from IRI. Conversely, recipients lacking pre-sensitization are significantly more likely to experience IRI and produce DSA post-transplant. Clinicians should therefore consider increased baseline and post-transplant monitoring for LT recipients, especially those without evidence of HLA pre-sensitization.