Abstract
Allogeneic HSCT (allo-HSCT) is associated with serious side effects and its most common complication is graft-versus-host disease (GVHD). Hyperacute GVHD is a clinical syndrome that occurs within the first 14 days after allo-HSCT associated with significant morbidity and mortality. The large sample size of clinical study indicated that the incidence of hyperacute GVHD in patient who underwent an allo-HSCT was about 9%, but the pathological process and crucial factor of this complication have incompletely defined.
Myeloid-derived suppressor cells (MDSCs) have been found that had a beneficial role in treatment of GVHD, on account of suppressing ability on alloreactive T-cell-response in vitro and in vivo. It was reported that reactive oxygen species (ROS) have been implicated in MDSCs-mediated T cell suppression and MDSCs from NOX2-deficient mice, chronic granulomatous disease (CGD) mice, failed to suppress T cell function. However, the investigation of whether and how MDSCs and ROS play in CGD mice receiving allo-HSCT is lacking.
In our research, WT mice receiving allo-HSCT began to appear typical acute GVHD clinical manifestations in about 20 days and died within 30 days after transplantation, while CGD mice receiving allo-HSCT suddenly suffered from hyperacute GVHD at day 3 after allo-HSCT: performed continuous weight loss, demonstrated poor grooming and impairs movement with or without hunching or skin integrated and animals died within 2 days after onset of symptoms. Further study shown that the donor spleen derived T cells was indispensable for hyperacute GVHD of CGD mice after receiving allo-HSCT. T lymphocyte subsets and proportional change in bone marrow and spleen of each group were detected by flow cytommeter after transplantation. The percentage and absolute number of donor derived CD3+CD8+T cell from both BM and spleen of CGD were significant higher than that of WT mice received allo-HSCT. Moreover, cell size and expression of activation marker CD25, CD44, and CD69 of CD3+CD8+T cell from both BM and spleen of CGD mice were significant higher than that of WT mice. The killing ability of donor derived CD3+T cells was observed by the living cells workstation and it was obviously to see that allo-reactive T cells from CGD mice had stronger killing ability. The levels of different cytokines in serum of recipient mice were detected by protein chip at day 3 after allo-HSCT. Comparing to C57BL/6 mice, more than ten kinds of inflammatory factors, including IL-6, were increased in the serum of CGD mice, which indicated that the cytokine storm related to T cells might be occur during hyperacute GVHD. In addition, using this hyperacute mouse model, we revealed that application of ROS agonist, L-buthionine-S, R-sulfoximine (BSO), rescued the CGD mice receiving allo-HSCT from hyperacute GVHD.
In General, this study pioneering established a stable murine model of hyperacute GVHD and proved that allo-reactive T cells massively activated and proliferated since ROS production defective MDSCs lose the ability of inhibiting T cell immune reaction and caused hyperacute GVHD. These data provided new insights into the pathogenesis of GVHD and may improve the clinical management of this common complication.
Disclosures
No relevant conflicts of interest to declare.
Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease
