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

Zeun J, Bernhardt AL, Neubeck S, Lang V, Korn K, Nagel L, Kunert T, Brey S, Atreya I, Denzin L, Bäuerle T, Hildner K, Büttner-Herold M, Winkler T, Mackensen A, Reimann H, Kremer A (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Transplantation and Cellular Therapy Elsevier

Book Volume: 31

Pages Range: 584.e1-584.e12

Journal Issue: 8

DOI: 10.1016/j.jtct.2025.04.022

Abstract

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.

Authors with CRIS profile

Julia Zeun Professur für Genetik Anna Luise Bernhardt Lehrstuhl für Genetik Katharina Korn Department of Medicine 5 – Haematology and Oncology Timo Kunert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefanie Brey Lehrstuhl für Genetik Imke Atreya Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Tobias Bäuerle Professur für Multimodale Bildgebung in der präklinischen Forschung Kai Hildner Professur für Mukosale Immuntherapie Maike Büttner-Herold Department of Nephropathology Thomas Winkler Professur für Genetik Andreas Mackensen Lehrstuhl für Innere Medizin V Hannah Reimann Department of Medicine 5 – Haematology and Oncology Anita Kremer Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Rutgers, The State University of New Jersey US United States (USA) (US)

How to cite

APA:

Zeun, J., Bernhardt, A.L., Neubeck, S., Lang, V., Korn, K., Nagel, L.,... Kremer, A. (2025). Selective H2-O Tissue Expression Reduces Risk for Graft-versus-Host Disease in an In Vivo Transplantation Model. Transplantation and Cellular Therapy, 31(8), 584.e1-584.e12. https://doi.org/10.1016/j.jtct.2025.04.022

MLA:

Zeun, Julia, et al. "Selective H2-O Tissue Expression Reduces Risk for Graft-versus-Host Disease in an In Vivo Transplantation Model." Transplantation and Cellular Therapy 31.8 (2025): 584.e1-584.e12.

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