HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Abstract

When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.

Figure 1

Molecular targets of GVHD and GVL after HCT from HLA-matched siblings or UD. HLA molecules and mHAg peptides are depicted as Y or bars, and APCs and T cells as large or small oval shapes, respectively. T cells that undergo positive or negative selection in the thymus are labeled with a T or an X, respectively. Self-peptides presented by HLA molecules on the surface of an APC are indicated with gray dots; mHAg peptides are indicated with orange or pink dots. (A) Genotypically HLA-matched siblings. In the left top box, the 2 parental HLA haplotypes are schematically represented, along with 2 examples of mHAgs of which 1 is shared (gray bars) and the other is not shared (orange and pink bars) by the 2 siblings. In the bottom box, the T-cell repertoire of the sibling donor after thymic education is shown. Self-reactive T cells against HLA molecules have been clonally deleted by negative selection, whereas T cells alloreactive to the unshared mHAg (pink T cells) have undergone positive selection and mediate GVHD and/or GVL after HLA-matched sibling HCT. (B) HLA-matched UD. The top box shows the HLA component of a typical 10 of 10 UD-recipient pair matched for both HLA-A, -B, -C-DRB1 alleles (in black and gray) as well as for the LEL-DRB3/4/5 and -DQ (in dark and light green), but mismatched for both LEL-DPB1 alleles (in dark and light blue and red, respectively). Moreover, in this example, patient and donor are mismatched for the same mHAg as in panel A. The bottom box shows the donor T-cell repertoire after positive and negative selection, which contains T cells alloreactive not only to mismatched mHAgs but also to both mismatched LEL-DPB1 alleles. In this example, 1 of the 2 mismatched HLA-DPB1 alleles is nonpermissive (dark red) whereas the other one is permissive (light red), giving rise to direct T-cell responses of different magnitude but generally stronger than the response to mHAg mismatches. Together, these alloreactive T cells mediate GVHD and/or GVL after HLA-matched UD-HCT.