GvHD: uncoupling immunopathology from the graft-vs-leukemia effect.


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Burkhard Becher1
1University of Zurich

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective treatment for several hematologic malignancies, but can result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking non-malignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically decouple GvL from GvHD. Here we show that the granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by allogeneic T cells exerts a distinct immune effector mechanism that separates the two processes. As such, GM-CSF drives GvHD pathology directly through engrafted phagocytes, producing inflammatory mediators such as IL-1β and ROS, leading to tissue damage. In contrast, GM-CSF had no impact on T cell activation or their capacity to eliminate leukemic cells, retaining undiminished GvL responses. Lastly, tissue and liquid biopsies from patients with grade IV GvHD showed an elevation of GM-CSF-producing T cells, suggesting that GM-CSF-neutralization has great translational potential in allo-HCT.