IL-17-Producing T Cells Contribute to Mediate Acutegraft-Versus-Disease In Patients Undergoing Unmanipulated Blood and MarrowTransplantation

Abstract 2310

Acute GVHD is a proinflammatory process mediated in part by mature donor T cells present in the stem cell or marrow inoculums that are polarized toward a Th1 phenotype and recognize minor or major histocompatibility disparities between the donor and host. A large amount of data has clearly shown that a newly identified subset of interleukin (IL)-17-producing CD4 T lymphocytes, named TH-17 cells, play a crucial role in triggering inflammation and tissue injury in various autoimmune diseases. The role of TH17 cells in acute GVHD had been controversial in recent mice and human transplantation. The aim of this study was to investigate the effects of IL17-producing T cells, including Th17 and Tc17 cells, on GVHD in patients receiving granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBPCs) and G-CSF-primed bone marrow (GBM) transplantation. Forty-one patients were analyzed according to the Th17 and Tc17 cell content in allograft in relation to aGVHD. Furthermore, ten patients with acute GVHD onset were monitored for the presence of Th17 cells by flow cytometry in the peripheral blood. Patients who subsequently developed aGVHD have greater proportions and doses of Th17 and Tc17 cells in GBM and PBPCs allograft infused into the patients (p=0.049 and 0.029 for Th17 in GBM; p=0.078 and p=0.033 for Tc17 in GBM; p=0.103 and 0.008 for Th17 in PBPCs; p=0.007 and 0.001 for Tc17 cells in PBPCs). At the same time, there were also significantly higher proportions and doses of Th1 and Tc1 cells in GBM and PBPCs allograft in patients with aGVHD compared with those levels in patients without aGVHD. Acute GVHD occurred 20 patients occurred, among which were 2 patients with gastrointestinal GVHD, 4 patients with skin plus gastrointestinal GVHD and the 14 others with simple skin GVHD. When we further compared patients according to the aGVHD target organ, we also found the significant association between dose of IL17 producing T cells (Th17 and Tc17) and the occurrence of simple skin GVHD. Cox regression models demonstrated that dose of Th17 in GBM (RR 1.095, CI 1.032– 1.162, P=0.003), dose of Tc17 in PBPCs (RR 1.063, CI 1.017– 1.112, P=0.008) and the number of HLA locus mismatch (RR 1.84, CI 1.18– 2.87, P=0.008) emerged as the independent factors influencing the occurrence of aGVHD. Patients receiving a higher dose of Th17 cells in GBM allograft (>8.5×10⁴/kg, p=0.005), and Tc17 cells in PBPCs (>16.8×10⁴/kg, p=0.001) exhibited a higher incidence of aGVHD. An increased Th17 population (up to 4.99% of CD4 T lymphocytes) was observed in patients with acute GVHD onset. In contrast, the percentage of Th17 cells drastically decreased in GVHD patients when they were treated to achieve partial and complete remission (p=0.013 and p=0.008, respectively). All percentages of Th17 and Tc17 were significantly reduced after G-CSF in vivo application. Our results suggest IL-17 producing T cells contribute to mediate aGVHD. Furthermore, G-CSF in vivo application helps to reduce the occurrence of aGVHD through reducing the secretion of IL17 in T cells.