Restoration of murine cytomegalovirus (MCMV) induced myelosuppression by AS101.

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. The gravest danger for the host occurs when the virus is reactivated as a result of immunosuppression. In this report we studied the effects of sublethal murine cytomegalovirus (MCMV) infection on the hemopoietic system including bone marrow (BM) cellularity, production of colony stimulating factor (CSF) and interleukin-6 (IL-6) and the development of granulocyte-macrophage colony forming units (CFU-GM), and BM stromal cell viability. Our findings show that the virus infection led to a significant decrease in the number of BM cells and in the production levels of CSF and IL-6. There was also a decrease in the number of stromal cells, as reflected by the number of colony forming unit fibroblasts (CFU-F), and in the relative number of CFU-GM progenitors. Treatment of MCMV infected mice with the immunomodulator AS101 [ammonium trichloro (dioxyethylene 0-0')tellurate] restored significantly CSF and IL-6 production by BM cells to levels of uninfected control mice as well as the number of CFU-F and stromal cell elements which consequently led to the restoration of the total number of BM cells. Results presented here indicate that AS101 may have immunomodulatory effects on MCMV mediated myelosuppression. Administration of AS101 to patients with CMV associated BM damage may improve the restoration of their BM function.

Protective and restorative role of AS101 in combination with chemotherapy.

The immunomodulator AS101 has been found previously by us to stimulate the secretion of high levels of interleukin 1 and colony stimulating factor (CSF) in vitro, as well as the production of CSF in vivo in mice models. These cytokines are known to induce proliferation and differentiation of hematopoietic progenitor cells from the spleen and bone marrow (BM) and to protect mice from DNA-damaging agents. The present studies were designed to evaluate the effects of prolonged treatment with AS101 on myelopoiesis, BM cellularity, and CSF secretion in mice treated with a sublethal dose of cyclophosphamide (CYP) and on the survival of mice undergoing treatment with lethal doses of this compound. In this model, the hematopoietic progenitors were suppressed during the overbound phase of myelopoiesis resulting from the cytotoxic effects of CYP. This allowed the detection of a significant proliferative effect of AS101 in vivo on BM colony-forming units granulocyte-macrophage progenitor cells, BM cellularity, and the secretion of CSF. Moreover, AS101 protected these animals from the lethal effects of high doses of CYP. These protective effects were demonstrable only when AS101 was administered to mice prior to CYP treatment. The only exception was CSF secretion by spleen cells that had been reconstituted when AS101 was administered both prior to and following CYP treatment. AS101 was found to have a synergistic effect with CYP in the treatment of tumor-bearing mice, suggesting that the combination of these two modalities provides a more effective treatment of their tumors. These results strongly suggest an immunoregulatory role for AS101 in counteracting the chemotherapy-induced hematopoietic suppression as well as usefulness as adjunct treatment of cancer when used in combination with CYP.

Radioprotective effects of the immunomodulator AS101.

Ammonium trichloro(dioxyethylene-O-O')tellurate (AS101) is a new synthetic compound previously described by us as having immunomodulating properties and minimal toxicity. Clinical trials are currently in progress with AS101 on AIDS and cancer patients. We found that AS101 was capable of inducing spleen cells and peritoneal exudate cells to secrete high quantities of CSF and IL-1. Because IL-1 has been previously described as a radioprotector and CSF may induce in vivo the proliferation of hemopoietic cells, we designed the present study in order to evaluate the effects of prolonged in vivo injections of AS101 on protection against lethal doses of irradiation, on the recovery pattern of precursor cells, and on the functioning of bone marrow (BM) and spleen cells of mice undergoing sublethal doses of treatment. We demonstrate that pretreatment with AS101 protects mice from lethal effects of ionizing radiation. AS101 was also found to significantly increase the number of BM and spleen cells, the absolute number of granulocyte macrophage-CFU and the secretion of CSF by BM cells. All were tested 9 days after sublethal dose of irradiation was administered. AS101 was found to have all of these radioprotective effects only when administered to mice before irradiation treatment. Moreover, the compound was found to enhance the proportion of CFU-S that enters the S phase of the cell cycle. These findings indicate that AS101 may be a promising agent to be used in reducing the time needed for reconstitution of hemopoietic cells after irradiation treatment.

The effect of a single whole-blood transfusion on cytokine secretion.

The effect of a single whole-blood transfusion on the cascade of cytokine secretion was studied in patients with chronic renal failure. The results indicate that 1 week after blood transfusion, no significant changes were observed in the secretion of interleukin-2, colony-stimulating factor, tumor necrosis factor, and gamma-interferon. However, 2 weeks after blood transfusion, a sharp decrease was observed in the generation of these cytokines. A decrease of about 70% was observed in interleukin-2, tumor necrosis factor, and gamma-interferon secretion. The production of colony-stimulating factor 2 weeks after blood transfusion amounted to about 30% less than baseline levels. No statistical differences in interleukin-1 production were observed throughout the study. In addition, we found that the decrease in cytokine secretion was paralleled by a sharp increase in the in vitro secretion of prostaglandin E2. Thus the beneficial effect of blood transfusion on graft survival might be due in part to an immunosuppressive effect brought about by immunoregulatory changes via the cascade of cytokine secretion.