Liposomes for manipulation of macrophage functions

The selective targeting of immunomodulators to appropriate sites of action is an integral and important component of immunotherapy for infectious diseases and cancer. Most attempts to target liposomes to solid tumors have been disappointing because the phospholipid vesicles are unable to reach organ parenchyma, since they are not able to cross the barriers formed by capillary walls. Also, they are rapidly endocytosed by phagocytic cells. However, taking advantage of this natural fate of liposomes to target immunomodulators to cells of the mononuclear phagocyte system, Fidler and colleagues were able to activate these cells to a tumoricidal or virucidal state. Systemic administration of liposomes containing various immunomodulators has been shown to bring about regression of lymph node, lung and liver metastases, and dramatic prophylaxis of viral infections in rodents.

Macrophages perform a wide variety of functional activities in immune reactions. They have an important role in the clearance of immune complexes and apoptotic T and B lymphocytes and they are involved in processing of particulate antigens. In addition they play a crucial role in the differentiation of several nonphagocytic cells and in the regulation of their functions. These latter roles are dependent upon the production of a number of cytokines and other soluble mediators by the macrophages. Recent studies have shown that, for example, in the liver, macrophages (Kupffer cells) are responsible for the bulk of all lipopolysaccharide-induced interlcukin If} (IL-ip), IL-6, IL-10 and IL-12 mRNA expression. Macrophages form a heterogeneous cell population. In the spleen for instance, red pulp macrophages, marginal zone macrophages, marginal metallophilic macrophages, white pulp macrophages and ringible body macrophages show a compartment-specific localization pattern. In addition, they can be distinguished by different surface markers, a different morphology and by differences in their functional specialization.

Selective in vivo depletion of macrophages is a widely accepted approach used to investigate whether macrophages are involved in any particular biomedical process. Since the effects of the usual methods for macrophage depletion, such as treatment with silica, carrageenan, antimacrophage antibodies etc. were neither selective nor complete, we developed a new approach, based on the liposome-mediated intraphagocytic delivery and accumulation of the bisphosphonate clodronate. Macrophages ingest the lipsome-encapsulated clodronate and then disrupt the phospholipid bilayers using their lysosomal phospholipases (see Figure 2). The encapsulated clodronate is then released within the cell and since clodronate molecules do not easily escape from living cells, the drug is accumulated intracellularly. Finally, the cell death programme is activated, leading to elimination of the cell by apoptosis. Using this so-called liposome-mediated macrophage 'suicide'

in reactions.

Figure 2 Liposomes, encapsulating clodronate or other water-soluble molecules (squares) in their aqueous compartments, are ingested by macrophages. After fusion of the liposome-contain-ing endosome with lysosomes (L) containing phospholipases (arrowheads), the latter disrupt the phospholipid bilayers of the liposome. The more the concentric bilayers of the liposome are disrupted, the more the encapsulated molecules are released within the cell. N, nucleus.

transient suppression of macrophage activity. This may be particularly relevant to the role of macrophages in the induction of inflammation, since the macrophage-derived cytokines IL-1 and tumor necrosis factor a (TNFa) appear to play a crucial role in the induction of various inflammatory in reactions.

See also: Adjuvants; Hapten; Immunoassays; Immun-opotentiation; ISCOM (immuno-stimulating complex); Macrophage activation; Phagocytosis.

Figure 2 Liposomes, encapsulating clodronate or other water-soluble molecules (squares) in their aqueous compartments, are ingested by macrophages. After fusion of the liposome-contain-ing endosome with lysosomes (L) containing phospholipases (arrowheads), the latter disrupt the phospholipid bilayers of the liposome. The more the concentric bilayers of the liposome are disrupted, the more the encapsulated molecules are released within the cell. N, nucleus.

approach, it has been established for instance, that alveolar macrophages actively suppress the function of dendritic cells in the lung, that liver macrophages play a role in the differentiation of liver-specific NK cells and that testis macrophages play a role in the differentiation of Leydig cells.

It is anticipated that, apart from effects mediated by physical depletion of macrophages from tissues, encapsulated drugs (in sublethal doses for macrophages) may also prove to be useful in the

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