ROS Deficiency Exacerbates Donor T Cell-mediated hyperacuteGVHD And Its Predictive Value in Allogeneic HSCT in Human Patients.

Background: Hyperacute graft-versus-host disease (GVHD) as a severe and lethal disorder frequently occurs within 2 weeks followed by allogeneic haematopoietic stem-cell transplantation (allo-HSCT). Molecular mechanisms underlying allo-HSCT triggered hyperacute GVHD remain elusive. Method: Using a genetic NADPH-oxidase deficient CGD murine hyperacute GVHD model, we measured the proportion and related function of donor-derived T cells and recipient-derived myeloid derived suppressor cells(MDSC) by flow cytometry. Reactive oxygen species(ROS), a key molecule of immunosuppressive function, was evaluated by luminometer in murine model and cohort patients who received allo-HSCT with or without hyperacute GVHD. We also performed related interventions such as MDSC depletion and ROS agonist to discern the clinical significance of MDSC-NADPH-ROS axis on immune homeostasis. The underlying mechanism on the process of hyperacute GVHD was determined by RNA-sequence assay and cytokine profiling. Results: : Here we surprisedly found that MDSC derived ROS potently prevents hyperacute GVHD by suppressing T cells activation. Moreover, in CGD mice receiving transplantation, the donor derived T cells triggered an immense allo-reactive T cell response and gained killing capacity during hyperacute GVHD. MDSCs, a main cell type for ROS production, exhibited defective suppressive effects on CD8 + and CD4 + T cells. Similarly, pharmacological depletion of MDSCs by an anti-Gr1antibody reproduced the hyperacute GVHD phenotype as seen in CGD mice. Conversely, a gain-of-function approach using a ROS agonist prevented development of hyperacute GVHD. Transcriptional analysis showed that T-cell dysregulation during hyperacute GVHD. In a cohort of 17 patients who received allo-HSCT, ROS levels were reversely correlated with hyperacute GVHD development. Together, our data provide novel mechanistic insights into the MDSC-NADPH-ROS suppressive functions in development of allo-HSCT. Conclusion: On the basis of these findings, we propose a new therapeutic paradigm by delivery of ROS agonists for effective prevention and treatment of hyperacute GVHD.