This project investigates the toxic and immunomodulating activities of a series of synthetic copolymers which are widely used industrial and domestic surfactants. They are composed of linear chains of polyethylene oxide attached in varying proportions to similar chains of polypropylene oxide in one of four configurations. Our previous studies demonstrated that certain of these copolymers form toxic surfaces analogous to those of quartz and the mycobacterial glycolipid trehalose 6,6'dimycolate. However, variations in copolymer structure were associated with marked changes in biologic activity. For example, one copolymer, T1501, forms a hydrophilic surface, activates complement, binds large amounts of protein, and is a powerful adjuvant for enhancing antibody formation. Another copolymer formed of the same components in the reverse order, T150R1, forms a relatively hydrophobic surface composed of liquid crystalline arrays. It does not activate complement and is not an adjuvant for increasing antibody production, but is toxic for macrophages and induces caseating granulomas. Other copolymers have distinctly different biologic activities such as the stimulation of anaphylactoid reactions or accelerated fibrosis. In several situations, correlations were identified between the surface physicochemical properties of the copolymers and their biologic activities. The twin goals of this project are to determine the biologic and physicochemical mechanisms through which these chemically similar polymers induce such diverse biologic reactions and to develop them as models of physicochemical mechanisms of toxicity which might be applicable to other materials.
The specific aims i nclude studies of 1) the relationships among germinal center hyperplasia, complement activation, anaphylactoid reactions and antibody production of a copolymer, L121, which is a particularly effective adjuvant, 2) the mechanisms by which copolymer T150R1 kills macrophages in vitro and induces granulomas and dissemination of coated beads in vivo, and 3) a study of copolymers and other materials which induce delayed type hypersensitivity. These studies are proceeding in three phases. The first is the development of optimum preparations for a particular activity. The second is an investigation of mechanisms through a process of correlation of biologic and physicochemical data. Finally, postulated mechanisms will be directly tested.
