*Purpose: Autoantibodies, which may be generated in transplantation through the exposure of cryptic antigens, are reported to be detrimental for allograft survival. We have demonstrated that pre-formed Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) are associated with poor allograft survival in liver retransplantation. Here we examine the effect of other pre-formed autoantibodies on graft survival after liver retransplantation.

*Methods: We studied a single-center retrospective cohort of 93 patients (1991-2018) who received second liver transplant. Pre-retransplant sera were tested with Luminex-based solid-phase assays for antibodies to 33 autoantigens. The primary outcome is survival of the second liver graft.

*Results: With follow-up for up to 25 years, 48/93 (51.6%) patients had lost second liver transplants. Seven autoantibodies were found to be significantly higher (p<0.05) in patients who lost grafts vs. whose grafts were still functioning. In univariate Cox regression, autoantibodies to LG3, a C-terminal fragment of Perlecan [HR=2.472 (1.376-4.44), p=0.002], Agrin [HR=1.83 (1.023-3.271), p=0.042], and Chromatin assembly factor 1 subunit B [HR=2.356 (1.053-5.275), p=0.037] were found to be associated with poor graft survival. In the multivariate model adjusting age and gender, LG3 autoantibody [HR=2.345 (1.105-4.980), p=0.027] and AT1R-AA [2.091 (1.066- 4.098), p=0.032] were significant and independent contributors for graft loss. 22/93 patients (23.4%) had positive autoantibodies to LG3, of which 18 (81.8%) had lost their grafts. In Kaplan-Meier analysis (Figure 1), patients with positive autoantibodies to LG3 had significantly worse graft survival (p=0.002) than those with negative LG3 autoantibodies.

*Conclusions: Autoantibodies to either LG3 or AT1R were found to be associated with inferior long-term outcomes of a second liver transplant. AT1R-AA causes vasoconstriction. Autoantibodies to LG3 are not yet defined as agonistic or antagonistic but have been shown to aggravate the ischemia-reperfusion injury and vascular rejection in kidney transplants. The detrimental effect of autoantibodies after transplantation may be mediated through their effect on graft and host vasculature.

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