Rodney L. Monroy

Granulocyte-macrophage colony-stimulating factor: More than a hemopoietin☆

Abstract : Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein with hormone-like properties and naturally occurring molecular mass between 14,500 and 35,000. The base polypeptide has 127 amino acids and its heterogeneity of molecular mass has been attributed to the degree of glycosylation. The glycosylation varies with the cell source but there does not appear to be specific biological roles for the different molecular species. Three different forms of the molecule have been cloned, produced in large quantities, and are currently under investigation in clinical trials. These recombinant forms are derived from a mammalian cell line (COS cells), bacterial cells (Escherichia coli), and yeast, each with varying degrees of glycosylation. The in vitro biological properties of these molecules does not appear to be different. This review is organized to present the effects of GM-CSF on normal hematopoiesis and its effect on mature myeloid cells. This will be followed by the results of clinical trials and the future applications of GM-CSF therapy. Keywords: Immunology, Cytokines, hemopoietins, Reprints.

Therapeutic evaluation of interleukin-1 for stimulation of hematopoiesis in primates after autologous bone marrow transplantation

A multiple dose IL-1 therapy was evaluated for its capability to stimulate hematopoiesis in normal primates and to restore hematopoiesis after autologous bone marrow transplantation. The administration of IL-1 to normal animals over a dose range of 0.5 to 10 ug/kg/d led to a 7-12 fold increase in peripheral blood neutrophil and monocyte counts after 24 hours. This increase in the mature peripheral blood myeloid cells was followed by changes in the myeloid composition of the bone marrow, where the percentage of myeloid elements increased along with a transient increase in myeloid progenitor cell activity. IL-1 treatment also led to an initial decrease in platelet counts of 10-30% during the first 3 days of treatment. However, a striking finding was a significant and long lasting stimulation of increased platelet production with platelet counts increasing to 77% of baseline 3 days after cessation of treatment and remaining elevated for the next 10 days. The therapeutic potential of the IL-1 regimen to restore hematopoiesis was further evaluated in an established autologous bone marrow transplantation model. In monkeys receiving IL-1 doses, 1.0 and 5.0 ug/kg/d, neutrophil counts recovered to >0.5 x 10e9/1 on day 16, one day earlier than control, but the recovery to baseline neutrophil counts occurred 5 days sooner than control. IL-1 therapy had its greatest effect on the restoration of platelet counts after transplantation, reaching >100 x 10e9/l by day 21, two weeks earlier than control. This work demonstrates that IL-1 therapy stimulates myelopoiesis but its most promising clinical application is the stimulation of platelet production.

Utility of interleukin-1 in therapy of radiation injury as studied in small and large animal models.

Summary and conclusionsOur results demonstrate that IL-1 promotes hematopoiesis in normal and radiation compromised animals. IL-1 protected mice from lethal hematopoietic syndrome when given before irradiation. Given after irradiation, IL-1 promoted recovery of mice and primates from radiation injury.A comparison of the effects of IL-1 in three different species indicated that hematopoiesis of mice, monkeys,and dogs is upregulated in a similar fashion by IL-1. These three species, however, vary greatly in their sensitivity to IL-1. Whereas mice and dogs tolerated doses greater than 1000 ⧎g/Kg of IL-1, 10 ⧎g/Kg of IL-1 in rhesus monkeys resulted in considerable toxic effects.Several activities of IL-1 may explain its bone marrow restorative properties. The induction with IL-1 of several hematopoietic growth factors: GM-CSF, G-CSF, M-CSF, IL 3, and IL 6, clearly contributes to the accelerated growth and differentiation of hematopoietic progenitor cells. The induction of scavenger proteins may serve to reduce post irradiation oxidative damage.Our work raised a number of additional questions concerning the potential therapeutic utility of IL-1. The ability of IL-1 to promote engraftment of allogeneic bone marrow cells will require further study. The optimal dosage, schedule, and route for IL-1 induction of hematopoiesis will need to be established. The observed synergy of IL-1 with TNF, IL 6, or CSFs may be useful in reducing the requisite doses of cytokines from pharmacological to physiological levels with concomitant reduction in toxic effects. The choice of proper cytokine combinations, however, may also be dependent on the clinical status of the patients.

Differential augmentation of in vivo natural killer cytotoxicity in normal primates with recombinant human interleukin-1 and granulocyte-macrophage colony-stimulating factor.

The effect of recombinant human interleukin‐1 (IL‐1) alpha, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and combined factor therapy (CFT) on Rhesus monkey peripheral blood natural killer (NK) activity in vivo was compared. During a 14‐day treatment period, IL‐1‐treated animals demonstrated a 170% increase in NK activity against K562 target cells by day 4, reaching maximal levels (300%) at day 16, and returning to baseline by day 30. NK activity of GM‐CSF‐treated monkeys increased slightly (60–100%) during days 4–12. as did saline‐treated monkeys, but returned to baseline values by day 16. A delayed increase in NK activity resulted after GM‐CSF treatment, reaching a peak (260%) on day 23 and remaining elevated through day 39. CFT resulted in a bimodal response pattern, with two peaks of NK activity, one at day 16 and a second at day 39, The first peak of activity (223%) was significantly less than the activity attained with IL‐1 alone; the second peak (300%) was of greater duration and occurred later than the peak observed in GM‐CSF‐treated monkeys. Unlike IL‐1, GM‐CSF treatment did not lead to a immediate stimulation of NK activity; augmentation was delayed by more than 7 days post treatment. CFT results suggest that GM‐CSF reduced the direct NK response to IL‐1; while IL‐1 led to an enhanced delayed NK response. Therefore, IL‐1 and GM‐CSF augment NK activity through different but interrelated pathways.

Acute Lethality and Radiosensitivity of the Canine Hemopoietic System to Cobalt-60 Gamma and Mixed Neutron-Gamma Irradiation

Extrapolation of data obtained from model animal systems to predict the human biological response to ionizing radiation and subsequent stressors, such as trauma and/or infectious disease, remains a difficult problem. The choice of animal model is critical in making reliable decisions concerning diagnosis and treatment following single or combined injuries. The canine plays a central role as an appropriate large animal model for extrapolation of the human response to a variety of stressors, whether radiation alone, or in combination with some form of trauma.

Rescue of Lethally Irradiated Animals

Three recent radiation accidents—the reactor explosion in Chernobyl, U.S.S.R.,1 the external and internal cesium-137 exposure in Goiânia, Brazil,2 and the cobalt-60 exposure of three technicians in El Salvador, San Salvador—exemplify the usual conditions of accidental radiation exposure. The exposure environment is ill defined and uncontrolled.3 The radiation delivery is heterogeneous and nonuniform, and may vary in rate, quality, and energy. It is the uncontrolled nature of the radiation exposure, in addition to the potential for shielding, that forecasts the possible sparing of cells essential for survival, i.e., the stem cells of the hematopoietic system and the gastrointestinal system. Radiation experiments in which areas of the bone marrow were shielded have demonstrated the potential of spared bone marrow cells to repopulate the hematopoietic tissue and to increase not only the production of granulocytes and platelets but also the chances of surviving an otherwise lethal dose of radiation.4–11