Life-Long Administration of Liposomes and Lipid A in Mice: Effects on Longevity, Antibodies to Liposomes, and Terminal Histopathological Patterns

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Abstract
Long-term effects of life-long (>2 year) repeated intravenous injections (up to 17) of high doses of liposomes, lipid A, or liposomes containing lipid A were assessed in BALB/c mice. the liposomes contained dipalmitoylphosphatidylcholine, and cholesterol (1/0.75). When compared with mice injected only with normal saline, there were no statistical differences in life spans observed between the different groups. Animals injected with liposomes or liposomes containing lipid A gradually developed “ruffled” fur, but the animals did not appear sick otherwise, and no differences were observed in the mean weights of the animals in the different groups. All of the animals that were tested in each group, including those injected with normal saline, developed IgG antibodies against one or more of nine lipid antigens. the antibodies were detected by a solid-phase enzyme-linked immunosorbent assay (ELisA) and the antigens consisted of either lipid A or one of eight different phospholipids. After 765 days, when approximately half of the animals had died spontaneously, the surviving animals were sacrificed and subjected to extensive histopathological analysis. In each group (including the normal saline group) certain animals exhibited pathological changes in liver, spleen, or lung that might be expected to occur in highly aged animals. Approximately half of the animals in each group had lymphoproliferative disorders (hyperplasia and/or lymphoma). However, there were no bone marrow abnormalities, and no hepatic or splenic granulomatous reactions were found in any of the animals. From a pathological standpoint the groups were indistinguishable from each other. We conclude that life-long repeated injection of liposomes, lipid A, or liposomes containing lipid A does not alter longevity or cause any overt pathological changes in mice. We also conclude that antibodies to lipid A and a variety of phospholipids occur spontaneously in aged mice that have been injected only with normal saline.