Indirectly Recognized HLA-C Mismatches and Their Potential Role in Transplant Outcome

Abstract

HLA-C mismatches are clearly associated to alloreactivity after hematopoietic stem-cell transplantation; in a number of large cohorts, HLA-C mismatches are correlated to an increased risk of acute graft-versus-host disease (GVHD) or even impaired survival. While for HLA-A and -B, both antigenic as well as allelic mismatches are associated with an increased risk of acute GVHD, such an increased risk is only observed for antigenic HLA-C mismatches and not for allelic mismatches. These observations raise the question what sets HLA-C apart from HLA-A and -B. The difference may well be related to the reduced levels of cell-surface expression of HLA-C as compared to HLA-A and -B, possibly due to, among other factors, a limited peptide-binding capacity. This limited peptide-binding capacity may retain HLA-C in the ER and enhance degradation of the HLA-C protein. Once degraded, HLA-C-derived peptides can be presented to the immune system via other HLA alleles and are thus available for indirect recognition. Indeed, such HLA-C-derived peptides have previously been eluted from other HLA alleles. We have recently developed an approach to predict indirect recognition of HLA molecules, by establishing the numbers of predicted indirectly recognizable HLA epitopes (PIRCHES). The number of PIRCHES presented on HLA class I and II (PIRCHE-I and -II, respectively), are highly correlated to clinical measures of alloreactivity, such as acute GVHD. In the present “Hypothesis & Theory,” we reviewed the current knowledge on HLA-C mismatches and alloreactivity. Moreover, we speculate about the role of direct and indirect recognition of HLA-C and the consequences for donor selection in HLA-C mismatched stem-cell transplantation.

Predicted Indirectly Recognizable HLA Epitopes Presented by HLA-DRB1 Are Related to HLA Antibody Formation During Pregnancy

“…We used a computational approach to predict the binding of HLA-derived epitopes to maternal HLA class II (19)(20)(21)23). In our cohort of 229 mother-child pairs, PIRCHE-II numbers were higher in HLA mismatches that elicited child-specific HLA antibodies than in HLA mismatches that did not elicit child-specific HLA antibodies (Figure 1).…”

“…Inspired by these findings, we developed an in silico model that predicts HLA-derived T helper epitopes. This model identifies allopeptides presented by HLA class II molecules, designated as predicted indirectly recognizable HLA epitopes presented by HLA class II (PIRCHE-II) (18)(19)(20)(21).…”

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

“…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.…”