The Impact of Donor Specific Antibodies on the Long-Term Liver Allograft after Pediatric Living Donor Liver Transplantation

Abstract

Introduction: The protocol biopsies of liver allograft revealed that some pediatric liver transplant recipients on the way of weaning of immunosuppressants (IS) showed fibrosis in their liver allograft though their blood examination indicated normal liver function tests. The method of evaluation for immunological state against donor-derived alloantigens after liver transplantation has not been established yet. The absence of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) has been expected as a promising biomarker for safe withdrawal of IS. In this study, we analyzed DSA in sera and the pathological findings of liver biopsies more than 12 months after pediatric living donor liver transplantation (LDLT) to elucidate the relevance of DSA against HLA to the late post-transplant liver allograft. Methods: 75 pediatric LDLT recipients were undertaken liver biopsies more than 12 months after operation in 2011; including 73 protocol biopsies and 2 episode biopsies. DSA in sera from those recipients were determined and quantified by single antigen beads method, where mean fluorescence intensity (MFI) over 1,000 was considered as positive. In pathological findings, each evaluation was blindly conducted by pathologists, and fibrosis was graded following Metavir fibrosis socring system. Results: Thirty-two recipients showed DSA in sera; the numbers of recipients with DSA against HLA class I, HLA class II, and both HLA calss I and class II (DSA-positive) were 2, 28, and 2, respectively, while 43 recipients did not show DSA (DSA-negative). MFI of DSA against HLA class I was not high; median 3520, (range 1170-6310). On the other hand, MFI of DSA against HLA Class II showed high; HLA-DRB1 9356, (2216-23140) and HLA-DQB1 20844, (2862-24834). The pathological findings of DSA-negative recipients were no remarkable finding in 14 (32.6%), idiopathic chronic hepatitis in 2 (4.7%), fibrosis in 20 (46.5%), and rejection including acute cellular rejection, late acute rejection, and central perivenulitis in 7 (16.3%). On the other hand, those of DSA-positive recipients were no remarkable finding in 1 (3.1%), fibrosis in 17 (53.1%) and rejection in 13 (40.6%). Most of normal finding of liver biopsy were showed in DSA-negative recipients. (p=0.002) The frequency of rejection was significantly higher in DSA-positive recipients than DSA-negative. (p=0.009) The fibrosis graded more than F2 was observed in 7 of DSA-negative (16.3%) and 12 of DSA-positive recipients (37.5%). (p=0.037) Conclusion: The existence of DSA in sera from pediatric LDLT recipients more than 12 months after operation has been related to severe fibrosis and allo-immune responses, such as acute cellular rejection and central perivenulitis. The measurement of DSA suggests that immunosuppressive therapy should be maintained or strengthened for DSA-positive recipients.