Abstract
Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34+ cells. FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory, T central memory, and T effector memory cells, as well as TH1 and TH17 cells. Anti-CD3/CD28 stimulated T cells derived from FasL-treated-MPBCs express lower levels of CD25 and secrete lower levels of IFN-γ as compared to control cells not treated with FasL. FasL treatment also induces apoptosis of transitional, naïve, memory and plasmablastoid B cells leading to a reduction in their numbers in the graft and following engraftment in transplanted mice. Most importantly, ex vivo treatment of MPBCs with FasL prior to transplant in conditioned NOD-scid IL2Rγnull (NSG) mice prevented GvHD while preserving graft versus leukemia (GvL) effects, and leading to robust stem cell engraftment.
Highlights
Allogeneic hematopoietic stem-cell transplantation (HSCT) can cure a wide range of malignant and non-malignant hematological diseases
As a prelude to the clinical use of Fas ligand (FasL) to prevent Graft versus host disease (GvHD) in patients undergoing stem cell transplantation, we have explored the effects of a brief (2 h) incubation of mobilized peripheral blood cell (MPBC) derived from healthy, adult donors with FasL on graft composition (T cell subsets, antigen-presenting cells, in vitro hematopoietic colony formation and CD34+ hematopoietic progenitor cells)
A small but statistically significant increase in the number of human CFU was observed in the bone marrow (BM) of mice transplanted with CD34+ cells derived from FasL-treated-MPBCs compared to the control treatment group at 4 weeks (Fig. 1l)
Summary
Allogeneic hematopoietic stem-cell transplantation (HSCT) can cure a wide range of malignant and non-malignant hematological diseases. A variety of in vivo or ex vivo modalities are available to prevent GvHD, but these same agents and procedures may attenuate immune reconstitution, increase the risk of infections and/or abrogate T-cell-mediated GvL effects [7, 8] It has been shown in both preclinical and clinical models that specific T cell subsets exert positive and negative control over the GvHD reaction. Askenasy et al demonstrated that ex vivo incubation of recipient- naïve donor mouse lymphocytes with FasL causes apoptosis of activated CD8 and CD4 cells with a concurrent increase in the regulatory T-cell (Treg) population [24] These authors showed that treatment of murine recipient-naïve haploidentical splenocytes with FasL in the context of F1 to hybrid transplantation led to lower clinical and histological GvHD scores of skin and gastrointestinal tract as compared with the fatal GvHD seen following the infusion of control splenocytes.
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