Abrogation of radiation injury to human hematopoietic stem cells with tumor necrosis factor-alpha.

Ionizing radiation kills hematopoietic stem and progenitor cells. However, several cytokines, including tumor necrosis factor-alpha (TNF-alpha), protect the murine hematopoietic system if they are introduced before or immediately after irradiation. We examined the in vitro capacity of TNF-alpha to protect human hematopoietic stem cells and early progenitor cells from x-ray-induced death. Human CD34+ cells obtained from normal bone marrow were highly enriched for stem and progenitor cells. Pulse exposure of these cells to human TNF-alpha during the first hour immediately after x irradiation (doses of 0.45 Gy to 9 Gy) significantly improved further survival of true hematopoietic stem cells and early progenitors and the ability of CD34+ cells to produce mature hematopoietic cells in liquid culture with hematopoietic growth factors. The radioprotective effect of TNF-alpha was stronger at lower doses, when complete restoration of hematopoiesis was often observed. In contrast, the radioprotective effect of TNF-alpha was moderate at higher doses, with neither complete restoration of the number of stem and progenitor cells nor the production of mature cells. Our data suggest that TNF-alpha can protect human hematopoietic stem and early progenitor cells from ionizing radiation.

The Chernobyl governmental program: two years of experience at the Belarusian Bone Marrow Transplant Centre.

The Bone Marrow Transplantation Program in Belarus was founded in 1992, and in 1993, a Bone Marrow Transplantation Centre was created in Minsk. From February 1994 to April 1996, 19 allogeneic bone marrow, 16 autologous bone marrow and 10 autologous peripheral blood stem cell transplantations were performed. Reasons for transplantation included chronic myeloid leukemia, multiple myeloma, severe aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, progressive myelofibrosis, Hodgkin's disease, non-Hodgkin's lymphoma, and neuroblastoma. Among the patients were two liquidators involved in the Chernobyl cleanup activity, both of whom underwent allogeneic bone marrow transplantation. A variety of ablative preparative regimens were used, and blood progenitor cells were mobilized by treatment with Cytoxan and granulocyte colony-stimulating factor. Therapy-related deaths resulted from graft-versus-host disease, septic shock, veno-occlusive disease bleeding and intestinal pulmonary fibrosis. Because the transplantation procedures were carried out on people who continued to be exposed to low-level irradiation, the post-transplantation period included a conservative strategy for prevention of graft-versus-host disease. There was nothing unusual about the post-transplantation period, although uncertainty about the continuing radiation dose should be taken into account when interpreting these data.

Ionizing radiation increases TNF/cachectin production by human peripheral blood mononuclear cells in vitro.

Human peripheral blood mononuclear cells (PBMC) and monocytes produce a large amount of tumor necrosis factor/cachectin (TNF) in vitro. Our data suggest that X-irradiation can increase TNF production by these cells. After 900 cGy irradiation there were 7-fold (24 h incubation) and 2.3-fold (48 h incubation) increases of TNF production by stimulated PBMC. The irradiation also increased TNF production by both stimulated and unstimulated human monocytes. These findings suggest that TNF overproduction can play an important role in the pathogenesis of radiation disease.