Refinement of the Definition of Permissible HLA-DPB1 Mismatches with Predicted Indirectly ReCognizable HLA-DPB1 Epitopes

Abstract

Hematopoietic stem cell transplantation with HLA-DPB1-mismatched donors leads to an increased risk of acute graft-versus-host disease (GVHD). Studies have indicated a prognostic value for classifying HLA-DPB1 mismatches based on T cell-epitope (TCE) groups. The aim of this study was to determine the contribution of indirect recognition of HLA-DP-derived epitopes, as determined with the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) method. We therefore conducted a retrospective single-center analysis on 80 patients transplanted with a 10/10 matched unrelated donor that was HLA-DPB1 mismatched. HLA-DPB1 mismatches that were classified as GVH nonpermissive by the TCE algorithm correlated to higher numbers of HLA class I as well as HLA class II presented PIRCHE (PIRCHE-I and -II) compared with permissive or host-versus-graft nonpermissive mismatches. Patients with acute GVHD grades II to IV presented significantly higher numbers of PIRCHE-I compared with patients without acute GVHD (P < .05). Patients were divided into 2 groups based on the presence or absence of PIRCHE. Patients with PIRCHE-I or -II have an increased hazard of acute GVHD when compared with patients without PIRCHE-I or -II (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.10 to 9.19; P < .05; and HR, 4.07; 95% CI, .97 to 17.19; P = .06, respectively). Patients classified as having an HLA-DPB1 permissive mismatch by the TCE model had an increased risk of acute GVHD when comparing presence of PIRCHE-I with absence of PIRCHE-I (HR, 2.96; 95% CI, .84 to 10.39; P = .09). We therefore conclude that the data presented in this study describe an attractive and feasible possibility to better select permissible HLA-DPB1 mismatches by including both a direct and an indirect recognition model.

How to select the best available related or unrelated donor of hematopoietic stem cells?

“…Indeed the number of peptides derived from incompatible HLA molecules presented by HLA antigens shared between the recipient and the donor can be predicted using the PIRCHE (predicted indirectly recognizable HLA epitopes) model. 33,34 In unrelated HSCT with HLA-C or -DPB1 mismatches, the number of PIRCHE has been reported to correlate with clinical outcome. 33,34 First-field versus second-field (antigen versus allele, or low versus high) mismatches…”

“…33,34 In unrelated HSCT with HLA-C or -DPB1 mismatches, the number of PIRCHE has been reported to correlate with clinical outcome. 33,34 First-field versus second-field (antigen versus allele, or low versus high) mismatches…”

Complete donor chimerism is a prerequisite for the effect of Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) on acute graft-versus-host disease

“…To investigate this hypothesis, we retrospectively studied a cohort in which a correlation between the presence of HLA-DPB1-derived PIRCHE and acute GVHD was shown previously. 6 In this latter study, patients with acute grade II-IV GVHD had significantly higher numbers of PIRCHE-I compared to patients with grade 0-I GVHD, and presence of PIRCHE-I and -II was associated with a higher probability of acute GVHD compared to absence of PIRCHE-I and -II. …”

“…6 In the present study, we stratified according to chimerism status and then studied the effect of PIRCHE presence on GVHD development. Of the 38 patients with complete chimerism, 18 (47%) had PIRCHE-I, and 25 (66%) had PIRCHE-II.…”

“…This so-called Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model predicts the numbers of peptides derived from the mismatched HLA molecules that can be presented on donor-patient shared HLA. [4][5][6] Thus, the number of PIRCHE equals the number of HLA-derived T-cell epitopes, and higher numbers of PIRCHE presented by HLA class-I or -II (PIRCHE-I or -II) have been correlated to acute GVHD development. 5,6 The presence of a vast majority of donor T cells in the patient's haematopoietic system is a significant predictor for acute GVHD, thereby underlining the essential role of alloantigen-specific donor T cells in the induction of GVHD.…”