Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Haploidentical stem cell transplantation(haplo-SCT)achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation(MSDT)in treating hematological malignancies.To define the underlying regulatory dynamics,we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension.First,we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility(MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo.We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden.The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor–α,interferon-γ,pore-forming proteins and CD107a secreted by T cells or natural killer cells.Furthermore,we conducted a prospective clinical trial which enrolled 135 patients with t(8;21)acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT.The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT.Ex vivo experiments showed that,1 year after transplantation,cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period.Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.

Th2 polarization in target organs is involved in the alleviation of pathological damage mediated by transplanting granulocyte colony-stimulating factor-primed donor T cells

Acute graft-versus-host disease(a GVHD)is caused by allo-activated donor T cells infiltrating target organs.As a regulator of immune function,granulocyte colony-stimulating factor(G-CSF)has been demonstrated to relieve the a GVHD reaction.However,the role of G-CSF-primed donor Tcells in specific target organs is still unknown.In this study,we employed a classical MHC-mismatched transplantation mouse model(C57BL/6 into BALB/c)and found that recipient mice transplanted with GCSF-primed T cells exhibited prolonged survival compared with that of the PBS-treated group.This protective function against GVHD mediated by G-CSF-primed donor T cells was further confirmed by decreased clinical and pathological scores in this a GVHD mouse model,especially in the lung and gut.Moreover,we found that Tcells polarized towards Th2 cells and regulatory T cells were increased in specific target organs.In addition,G-CSF treatment inhibited inducible co-stimulator(ICOS)expression and increased the expression of tolerance-related genes in recipient mice.Our study provides new insight into the immune regulatory effects of G-CSF on T cell-mediated a GVHD,especially for its precise regulation in GVHD target organs.