Impact of Multiple Minor Histocompatibility Antigen Differences on Graft-Versus-Host Disease and Relapse Risk in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients
BLOOD(2023)
摘要
BACKGROUND Success of allogeneic hematopoietic cell transplantation (alloHCT) is sharped by alloreactivity, i.e. the ability of donor T-cells to recognize particular recipient motifs as non-self and get activated. Donor T-cells recognizing recipient tissue can cause harmful graft-versus-host disease (GvHD) while activity against leukemic blasts can protect against relapse (GvL). In HLA-matched alloHCT, alloreacticity is driven by subtle nonpathogenic variants in natural proteins, socalled minor histocompatibility antigens (miHAgs), however, not all variants are immunogenic. METHODS To analyze the impact of mHAgs-differences on alloHCT outcomes, we selected a purely pediatric cohort of 102 HLA-matched allo HCTs transplanted between 2003 and 2017. Panel sequencing of 46 validated miHAgs was performed using Ilumina MiSeq, only variants in the graft-versus-host direction were considered. RESULTS In a logistic regression model for the whole cohort acute GvHD incidence was significantly dependent on the proportion of miHAg mismatches (all genes) with an 95%-CI 1.0263-1.1998, p=.01 and an odds ratio of 1.1066. From all variants tested, only mismatches in TRIM42 were significant as a predictor with a FDR <.05. Furthermore, proportion of mismatches was a predictor of all-cause mortality. Risk of relapse was evaluated by regression analysis for competing risks: proportion of miHAg mismatches failed to be predictive for relapse ( p=.37). However, looking at patients with acute lymphobastic leukemia (ALL) only (n=36), mismatches in hematopoiesis-restricted genes protected from relapse (95%-CI 1.0016-1.0712, p=.04, hazard ratio 1.0358). CONCLUSION Thus, in children GvHD and mortality seem to be related to the overall number of miHAg-differences whereas variants in hematopoiesis-restriced genes protect from ALL relapse. These data implicate that selection of TCRs with a specificity for hematopoietic miHAgs could be a way to improve GvL effect without increasing the risk of GvhD.
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