Effects of ex vivo activated immune cells on syngeneic and semi-allogeneic bone marrow transplantation in mice

Abstract

We have previously shown that a novel immunotherapy using ex vivo activated immune cells is capable of promoting survival and hematopoietic recovery in mice after combined chemotherapy and radiotherapy. In this study, we investigated whether the immunotherapy with ex vivo activated immune cells had the same beneficial effects after syngeneic and semiallogeneic bone marrow transplantation (BMT) in BALB/c mice subjected to a lethal dose of total body irradiation (TBI). Immune cells were cultured in vitro with a combination of cytokines and a calcium ionophore for 2 days and subsequently injected to mice daily for 4 days starting 1 day after BMT. The immunotherapy enhanced survival and multilineage peripheral blood recovery in BMT mice with limited numbers of transplanted bone marrow cells when a low dose of ex vivo activated immune cells were used. However, the beneficial effects were completely lost when a higher dose of the same therapeutic immune cells were tested, and instead the immunotherapy significantly exacerbated complications associated with the lethal radiation and BMT. This detrimental effect appeared to be the result of strong in vivo nonspecific immune responses induced by either activated therapeutic immune cells or interaction between therapeutic immune cells and MHC-mismatched bone marrow cells transplanted or both. Our data suggest that the immunotherapy with appropriately selected dosages may be beneficial to BMT but vigorous in vivo immune responses soon after BMT may exacerbate post-transplant complications.