Based on an extensive background of information obtained in vitro and in vivo in our laboratory, we believe that lactoferrin (LF) and transferrin (TF), two naturally occurring metal-binding glycoproteins, will be effective as biological response modifiers in the treatment of at least certain forms of leukemia. Information will be obtained on the production, release, and action of LF and TF in vitro from cells of patients with leukemia, neutrophilia, LF-deficiency, and bacterial infections in comparison to normal age-matched controls and from established cell lines. The structure-function relationship of LF and TF will be explored with regard to the need for sialic acid and carbohydrate moieties on the molecules and iron-saturation, in terms of receptor-binding and suppression of release of growth factors. The effectiveness of serum-LF and -TF before and after purification will be assessed. Production-release studies will use primary and/or HL-60 cells and the receptor-binding and activity studies will utilize primary and/or U937 or WEHI-3 cells. The expression of Ia-antigens and receptors for LF and TF on appropriate target cells will be correlated with responsiveness of the cells to LF and TF before and after shedding and gamma interferon (IFN?gamma?)-induction of Ia-antigens. The influence of LF and TF on phosphorylation of membranes will be evaluated using first U937 cells which will serve as a model for autocrine growth and production of growth factors that can be suppressed by LF and TF. LF or TF given in vivo results in approximately 50% long-term survival of mice infected with Friend Virus Complex (FVC). This is coincident with a drastic reduction in virus replication. LF and TF do not appear to inactivate the viruses directly. The efficacy of LF and/or TF will be assessed further in mice infected with FVC especially after inoculation of mice with agents such as IFN?gamma? which increase responsiveness of cells in vitro to LF and TF. The effectiveness of LF and TF in these mice will be correlated with presence, loss, and induction of Ia-antigens on target cells in vivo. The mechanisms of suppression of viral replication will be investigated on colony formation in vitro by cells infected in vitro or in vivo with FVC. (N)
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