Selective H2-O Tissue Expression Reduces Risk for Graft-versus-Host Disease in an In Vivo Transplantation Model.

BACKGROUND

Allogeneic stem cell transplantation (aSCT) is frequently used to treat patients with hematologic malignancies. The therapeutic effect relies mainly on the graft-versus-leukemia (GVL) effect, in which donor T cells eliminate residual malignant cells. Unfortunately, the beneficial GVL effect is often accompanied by detrimental graft-versus-host disease (GVHD). A successful separation of both effects could not yet be achieved. In previous work, we identified 2 groups of HLA-class II restricted antigens depending on their behavior towards HLA-DM. DM-resistant antigens are presented in the presence of HLA-DM, whereas presentation of DM-sensitive antigens relies on the inhibitory molecule HLA-DO. Due to the unique expression pattern of HLA-DO, DM-sensitive antigens cannot be presented efficiently by non-hematopoietic cells even under inflammatory conditions. This suggests that CD4+ T cells directed against DM-sensitive antigens may be able to separate GVL from GVHD.

OBJECTIVE

In this study, we wanted to demonstrate convincingly that HLA-DO expression strongly influences the severity of GVHD in allogeneic stem cell transplantation.

METHODS

We generated a modified CD4 donor lymphocyte infusion (DLI) depleted of CD4+ T cells directed against DM-resistant antigens to address its potential to induce GVHD in an in vivo major histocompatibility complex (MHC) mismatch transplantation model dependent on selective tissue expression of H2-O using H2-O wildtype, knockout, and transgenic recipients.

RESULTS

Intriguingly, we could demonstrate that our modified CD4 DLI targeting DM-sensitive antigens induced only mild GVHD in wildtype recipients with endogenous selective H2-O expression and none in H2-O knockouts while assessing the immunogenic potential of DM-sensitive antigens in H2-O transgenic recipients.

CONCLUSION

The results of the present work provide evidence that DM-resistant antigens are main targets of GVHD and addressing DM-sensitive antigens might be a promising tool to improve outcome after aSCT by separating GVL from GVHD.