Class II Human Leukocyte Antigen Epitope Mismatch Predicts De Novo Donor‐Specific Antibody Formation After Liver Transplantation

Abstract

Formation of de novo donor-specific antibodies (dn-DSAs) has been associated with longterm immunologic complications after liver transplantation (LT). We hypothesized that human leukocyte antigen (HLA) epitope/eplet mismatch (MM) is a marker of immunogenicity and a risk factor for dn-DSA formation. Sera from 80 LT recipients were prospectively screened for dn-DSA by a Luminex single-antigen test (One Lambda, Inc., Canoga Park, CA) at 1, 2, 3, 6, 12, 18, 24, and 36 months after LT. HLA typing of the recipients and donors was performed using polymerase chain reaction (PCR)-SSP and PCR-SSOP Luminex low-resolution methods (One Lambda, Inc.). The HLAMatchmaker computer algorithm was used for identification of MM eplets at HLA-DRB1 and -DQA1/B1 loci. Luminex single-antigen bead solid phase assay was used for antibody analysis. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus maintenance. There were 27 (34%) patients who developed dn-DSA. There were no episodes of antibody-mediated rejection, and 9 (11%) developed acute cellular rejection (ACR). A positive crossmatch status and a higher number of HLA-A, -B, -DR, and -ABDR MMs were not associated with dn-DSA formation. Patients developing dn-DSA had a significantly higher number of total (38 ± 2.7 versus 28 ± 2.3; P = 0.01) and antibody-verified (AbVer; 14 ± 1.1 versus 10 ± 1; P = 0.015) class II MM eplets. By a multivariate regression analysis, the number of class II MM eplets was strongly associated with risk of class II dn-DSA formation (odds ratio [OR], 1.2; P < 0.01). Patients with ACR had a significantly higher number of total (20.2 ± 1.3 versus 13.9 ± 0.9; P < 0.01) as well as AbVer (10.7 ± 1.1 versus 7.5 ± 0.6; P = 0.03) class I MM eplets. In conclusion, donor-recipient HLA epitope MM is associated with a risk of dn-DSA formation and rejection after LT. However, further studies are required to evaluate the clinical utility of epitope matching in LT.

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

“…It is unknown whether unique effector functions of IgG4 subclass DSA in the presence of higher HLA expression directly contributed to the subclinical histopathology phenotypes observed in these studies or whether a predominant IgG4 subclass serves solely as a biomarker of a prolonged smoldering humoral response. It is important to recall that higher HLA eplet mismatch loads were observed with DSA presence and strength, as previously reported,[31][32][33] and also with IgG4 subclass DSA. This is consistent with a scenario in which higher alloimmune burden drives DSA development and evolution over time to a more mature IgG4 humoral response.Our findings are consistent with other studies that have shown IgG4 DSA in recipients with chronically rejected kidney and liver allografts.…”

“…Patients with detectable class II DSA, compared to those without, had a higher median (interquartile range) total class II eplet mismatch (33 vs 26 ) and HLA-DQ alone mismatch (12 [8][9][10][11][12][13][14][15][16] vs 8 [4][5][6][7][8][9][10][11][12][13][14][15]). Similarly, total class II eplet mismatch was higher for those with MFI sum >20 000 vs ≤20 000 (40 [28-51] vs 28 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]). Among subjects with class II DSA, total class II eplet mismatch was higher for those with maximum MFI > 20 000 vs ≤20 000 (39 vs 30 [21][22][23][24][25][26][27][28][29][30]…”

“…Among subjects with class II DSA, total class II eplet mismatch was higher for those with maximum MFI > 20 000 vs ≤20 000 (39 [25-53] vs 30 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]). Similarly, total class II eplet mismatch was higher for those with MFI sum >20 000 vs ≤20 000 (40 [28-51] vs 28 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]). To further explore DSA attributes, which may aid in cluster prediction, we interrogated IgG subclass composition.…”

B cells in transplant tolerance and rejection: friends or foes?

“…The development of post‐transplant de novo DSA can occur in the absence of pretransplant HLA sensitization and has been shown to impact long‐term allograft survival. DSA that arises post‐transplant is primarily directed toward donor HLA class II mismatches and occurs in the setting of inadequate immunosuppression and/or increased HLA class II mismatching . The incidence of de novo DSA depends upon allograft type ranging from 12% in primary kidney transplants with a median time to development of 4 years and up to 30% in lung recipients within the first year post‐transplant .…”

PIRCHE-II: an algorithm to predict indirectly recognizable HLA epitopes in solid organ transplantation

“…Considerable research has been devoted to investigating the impact of the number of eplet mismatches between donor and recipient on HLA antibody formation and graft survival. Patients who were transplanted with a higher number of mismatched eplets have a higher risk for donor-specific HLA antibody formation after transplantation (Daniels et al 2018;Duquesnoy et al 2008a;Kubal et al 2018;McCaughan et al 2018;Walton et al 2018;Wiebe et al 2013). Moreover, additional studies suggest that matching based on the number of eplets may lead to an improved graft outcome in kidney (Wiebe et al 2013), heart (Sullivan et al 2015), lung (Walton et al 2016), liver (Ekong et al 2019), and cornea transplantation (Bohringer et al 2010).…”