Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice

Abstract

We and others have demonstrated that the milieu created by ionizing radiation (IR) used for conditioning plays a major role in the development of acute graft-versus-host disease (aGVHD). We reasoned that antioxidants that could inhibit IR induction of inflammatory cytokines and/or apoptosis might reduce the incidence or severity of aGVHD. Therefore, BALB/c mice were treated with amifostine, n-acetyl cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC) prior to transplantation with allogeneic C57Bl/6 bone marrow and spleen cells. None of 30 amifostine-pretreated mice developed weight loss or other signs of aGVHD and they rejected their allogeneic transplants. However, pretreatment to groups of five mice each with molar equivalent doses of NAC or PDTC accelerated death, and lower doses did not prevent aGVHD. In vitro tests demonstrated that PDTC and NAC acted as pro-oxidants when incubated with isolated normal mouse lymphocytes, whereas amifostine and its active metabolite WR-1065 did not. The conclusion that amifostine protected immune function from IR in vivo was further supported by the fact that amifostine and WR-1065 preserved the response of radiated normal lymphocytes to respond to PHA and both stimulated growth of non-radiated, non-PHA-treated normal lymphocytes in vitro. Taken together, these data caution the use of amifostine in allogeneic transplantation.