T‐cell infiltrate intensity is associated with delayed response to treatment in late acute cellular rejection in pediatric liver transplant recipients

Abstract

Background Late acute cellular rejection (ACR) is associated with donor‐specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. 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 (DR) to rejection therapy, we performed a single‐center retrospective case‐control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations. Methods Pediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy‐proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin‐fixed paraffin embedded (FFPE) liver biopsy tissue. Results Liver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti‐thymocyte globulin was only required in the DR group. The frequency of liver‐infiltrating CD20+ and CD8+ lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma‐glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR. Conclusions Higher serum GGT level, presence of autoantibodies, and increased CD8+ T‐cell infiltration portends DR in late ACR treatment in children.

Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

“…Our previous work implicated increased CD8 + T cell infiltrates in portal areas as a marker for delayed rejection treatment response (49). Here, we characterized the CD8 + T cell infiltrates and cellular interacting partners in an unbiased manner, utilizing single cell RNA sequencing combined with TCR V(D)J sequencing of cryopreserved liver biopsy tissue obtained from rejecting vs. non-rejecting pediatric liver transplant recipients.…”