Progressive graft fibrosis and donor-specific human leukocyte antigen antibodies in pediatric late liver allografts

Abstract

The role of donor-specific anti-human leukocyte antigen antibodies (DSAs) that develop late after living donor liver transplantation is unknown. Seventy-nine pediatric recipients who had good graft function and underwent protocol liver biopsy more than 5 years after transplantation (median ¼ 11 years, range ¼ 5-20 years) were reviewed. DSAs were determined with the Luminex single-antigen bead assay at the time of the last biopsy, and complement component 4d (C4d) immunostaining was assessed at the times of the last biopsy and the previous biopsy. The donor specificity of antibodies could be identified in 67 patients: DSAs were detected in 32 patients (48%), and they were usually against human leukocyte antigen class II (30 cases) but were rarely against class I (2 cases). These patients had a higher frequency of bridging fibrosis or cirrhosis (28/32 or 88%) than DSA-negative patients (6/35 or 17%, P < 0.001). Fibrosis was likely to be centrilobular-based. DSA-positive patients, in comparison with DSA-negative patients, had higher frequencies of diffuse/focal endothelial C4d staining (P < 0.001) and mild/ indeterminate acute rejection [15/32 (47%) versus 5/35 (14%), P ¼ 0.004]. Four DSA-negative patients were off immunosuppression, whereas no patients in the DSA-positive group were (P ¼ 0.048). In conclusion, the high prevalence of graft fibrosis and anti-class II DSAs in late protocol biopsy samples suggests that humoral alloreactivity may contribute to the process of unexplained graft fibrosis late after liver transplantation.

Prevalence, Incidence and Risk Factors for Donor-Specific Anti-HLA Antibodies in Maintenance Liver Transplant Patients

“…DSAs occurred in 9.05% of patients. Similar to previous reports, most patients (91%) developed anti-HLA class-II antibodies (16,18). We found that having a greater number of transplantations was an independent predictive factor for the formation of DSAs in LTs.…”

“…Musat et al (21) found an association between the presence of DSAs, positive C4d staining and the occurrence of biopsy-proven acute rejection. In pediatric stable maintenance LT patients, those with DSAs had a higher frequency of bridging fibrosis or cirrhosis, a higher frequency of diffuse/local endothelial C4d staining and mild/intermediate acute rejection compared to those with no DSAs (16). In our study, the liver fibrosis score was higher in patients with DSAs compared to those without DSAs.…”

“…The difference observed between Fontana et al's (15) study and ours is probably because we used a more sensitive assay. Recently, Miyagawa-Hayashino et al (16) assessed the prevalence of DSAs among stable pediatric LT patients who had survived for >5 years: they found a prevalence of 48% at 11 years (min-max: [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] posttransplantation. This high prevalence of DSAs is probably related to the very long follow-up in this Japanese study (16).…”

Antibody-mediated rejection in liver transplantation: Current controversies and future directions

“…60 Interestingly, centrilobular (perivenular) fibrosis in late biopsies (>5 years after transplantation) is not uncommon for pediatric LDLT recipients with circulating DSAs, and it may be reversible through an increase in immunosuppression. 25,61,62 If this mechanism of action is indeed effective, then extra caution must be observed for recipients who are enrolled in immunosuppression minimization or withdrawal trials. In a retrospective review of patients who had been off immunosuppression, those with circulating DSAs were found to be more likely to develop rejection.…”

Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

“…Protocol biopsies (PBs) from LT recipient children revealed frequent allograft inflammation and fibrosis (Evans et al, 2006;Scheenstra et al, 2009;Hubscher, 2011;Venturi et al, 2012Venturi et al, , 2014Gurevich et al, 2015), in stable LT recipients without predisposing factors (Evans et al, 2006;Venturi et al, 2014;Gurevich et al, 2015;Miyagawa-Hayashino et al, 2012). The etiopathogenesis of these "idiopathic" changes is unknown, while graft age, subclinical rejection and medication non-compliance have been considered as possible aetiologies (Hubscher, 2011;Venturi et al, 2014;Miyagawa-Hayashino et al, 2012). Among these, the donor specific class II HLA antibodies have been shown to play an important role in the allograft evolution.…”