*Purpose: Late acute cellular rejection (ACR) occurs >6mo post-liver transplant and is associated with chronic rejection and allograft loss. Currently, no diagnostic features predict ACR treatment response. ACR is primarily T cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response to rejection therapy, we performed a single center retrospective case-control study of pediatric late liver ACR using immunofluorescence for T cell, B cell, and PC markers.

*Methods: Pediatric liver-only transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between Jan 2014-Jan 2019 were stratified into rapid responders (RR) and delayed responders (DR) based on ALT normalization <30d (RR) or >30d (DR). All patients received IV methylprednisolone as initial rejection treatment. Anti-thymocyte globulin was used for treatment of steroid-refractory rejections exclusively in the DR category. No rejections led to graft loss. Banff score, medication level variation index (MLVI), and autoantibodies were analyzed for each ACR episode. We performed multiparameter immunofluorescence for CD4, CD8, CD20, and CD138 in FFPE liver biopsy tissue at the time of ACR diagnosis, and used logistic regression to determine if each cell count/hpf was associated with increased risk of DR compared to RR.

*Results: 60 liver biopsies in 54 patients were included in the analysis. 33 (55%) were DR, the average age at rejection was 10.8 years, the average time between rejection and transplant was 5.4 years, and the majority were transplanted due to biliary atresia (55%). Only one rejection episode occurred in a patient transplanted for autoimmune hepatitis. Based on univariate logistic regression analysis, treatment response was independent of Banff score and a lower MLVI was associated with decreased risk of DR (Table 1). However, a 10-fold increase in CD8 or CD4 count was associated with 2.9-fold and 2.05-fold the odds of DR compared to RR, respectively. Similarly, presence of ANA and ASMA autoantibodies at titers >1:80 were associated with 9-fold increased risk of DR (OR 9.136)

*Conclusions: Increased CD4 and CD8 counts in late ACR portal infiltrates may be early predictors of delayed response to anti-rejection treatment. While a larger sample size is required for validation, these results may point towards the benefit of early use of T-cell directed therapies for late ACR in high risk patients.

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