Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD

Abstract

DLI is traditionally used to provide graft-versus-leukemia (GvL) effects when given to patients relapsing post-hematopoietic cell transplantation (HCT). However, it is often associated with significant GvHD and has only modest efficacy against acute leukemias. Therefore, novel cellular therapies are needed to improve the outcome of high-risk or relapsed leukemia patients following HCT. Activated T helper-1 (aTh-1) lymphocytes are CD4 + CD25 + CD40L + CD62L lo effector memory cells that produce large amounts of IFN-γ and TNF-α. We demonstrate that post-transplant adoptive aTh-1 cell therapy enhances GvL with limited GvHD in an MHC-mismatched murine BMT model. aTh-1 infusions result in superior leukemia-free survival when compared with unstimulated splenocytes (SC), purified CD4 + T-cells and T-cell-enriched SC. aTh-1 cells display cytotoxicity against A20 leukemia cells in vitro and persist in vivo for at least 2 months following adoptive transfer. Furthermore, in contrast to unstimulated SC, aTh-1 cell infusion is associated with only transient, mild suppression of donor-derived hematopoiesis. aTh-1 cell therapy is safe, effective and warrants further investigation as an alternative to DLI.

Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells

“…Intestines were digested as described below. Flow cytometry was performed as described previously [37]. Fluorescence data were collected with an LSRFortessa cell analyzer (BD Biosciences) and analyzed using FlowJo 2 (Tree Star, Ashland, OR).…”

Post‐transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation

“…injection. A20 leukaemia and imaging A20, a BALB/c B-cell lymphoblastic leukaemia cell line (American Type Culture Collection, Manassas, VA, USA), is radio-resistant and has been used previously in murine BMT studies (Chen et al, 2006;Zeng et al, 2014). A20 was cultured in RPMI 1640 medium with 10% fetal bovine serum (FBS), MEM nonessential amino acids, and sodium pyruvate (Cellgro, Manassas, VA, USA) at 37°C and 5% CO 2 .…”

Graft‐Versus‐Tumor Effect in Major Histocompatibility Complex–Mismatched Mouse Liver Transplantation

“…Both HLA-mismatched HSCT and DLI have a stronger antitumor effect than HLA-matched HSCT, but they may also bring a greater risk of GVHD, one of the fatal complications after HSCT. (31)(32)(33)(34) Therefore, efforts have been made over the last 2 decades to explore the difference between the mechanism of GVT and GVHD and to design strategies to separate GVT from GVHD. (35,36) One important difference is that the threshold number of T cells triggering GVT is relatively lower.…”