Immunotherapy (IT) has become an accepted therapeutic modality. We previously reported that intracellular hyperthermia (IH) using magnetic nanoparticles induces antitumor immunity. We undertook these studies in order to study the combined effects of IT and IH on melanoma. Magnetite cationic liposomes (MCLs) have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs were injected into a B16 melanoma nodule in C57BL/6 mice, which were subjected to AMF for 30 min. The temperature at the tumor reached 43°C and was maintained by controlling the magnetic field intensity. At 24 h after IH, interleukin-2 (IL-2) or granulocyte macrophage-colony stimulating factor (GM-CSF) was injected directly into the melanoma. Mice were divided into six groups: group I (control), group II (IH), group III (IL-2), group IV (GM-CSF), group V (IH + + + +IL-2), and group VI (IH + + + +GM-CSF). yperthermia has been used for many years to treat a wide variety of tumors both in experimental animals and patients.1) The most commonly used heating method in clinical settings is capacitive heating using a radiofrequency (RF) electric field.2) However, specifically heating tumors by capacitive heating using an RF electric field is difficult, because the heating characteristics are influenced by various factors, such as tumor size, position of electrodes, and adhesion of electrodes at uneven sites. From a clinical point of view, a simple heat mediator is preferable for superficially seated tumors such as cutaneous melanoma. Magnetic nanoparticles have been applied to generate hyperthermia in an attempt to overcome these disadvantages.3, 4) These magnetic nanoparticles generate heat in an alternating magnetic field (AMF) due to hysteresis loss.
5)We have developed "magnetite cationic liposomes" (MCLs) for intracellular hyperthermia (IH).6, 7) MCLs were developed to show improved adsorption and accumulation in tumor cells and have a ten-fold higher affinity for tumor cells than for neutrally charged magnetoliposomes due to electrostatic interaction with the negatively charged cell membrane.6) In our in vitro experiments, 55% of MCLs were incorporated into cells and the intracellular magnetic nanoparticles could generate heat under AMF.6) We have also demonstrated the efficacy of IH using MCLs against T-9 rat glioma in an in vivo study.
8)We previously reported that our IH system induced antitumor immunity. 9) Hyperthermia is known to induce heat shock proteins (HSPs).10) Because expression of HSP70 protects cells from heat-induced apoptosis, 11) HSP70 expression has been considered to be a complicating factor in hyperthermia. On the other hand, recent reports have shown the importance of HSPs, such as HSP70, HSP90 and glucose-regulated protein 96, in immune reactions.12, 13) HSP-mediated antitumor immunity was reported to cause a vaccine effect due to HSP-peptide complexes purified from human melanoma cells.14) With regard to the mechanism of antitumor immunity induced by IH, we demonstrated th...
The retinal pigment epithelium (RPE) of 1- 24-month-old CF-1 mice was examined by both light and electron microscopy. Measurement of the area occupied by lysosomal bodies was carried out using a semiautomatic quantitative picture analyzing system (Kontron-EKO). Accumulation of lysosomal bodies in the apical RPE cytoplasm was the most characteristic feature in eyes over 12 months of age. The relative volume of lysosomal bodies to each RPE cytoplasm was maximal in 24-month-old mice RPE, approximately three times that of 3-month-old mice. Complicated lysosomal bodies and small lysosomal bodies were also observed in the dilated microvilli, in the apices of the apical RPE cytoplasm and in the subretinal spaces in eyes over 18 months of age. The passway and extrusive mechanism of lysosomal bodies are discussed.
The ultrastructural characteristics of ciliary epithelium from bovine, pigmented rabbit, and fetal albino rabbit were studied in cultured explants. The tips of ciliary processes were cultured in plastic dishes with Dulbecco Modified Eagle Medium (DMEM) containing 5% fetal bovine serum. More than half of the explants adhered to the plastic culture dish, and epithelial cells spread as monolayers within a few days. Initially the explant contains two layers, the outer (nonpigmented cells) and the inner (pigmented cells). Later the explant exhibits three layers: 1) outermost lightly pigmented flattened cells, 2) an outer layer of non-pigmented cells, and 3) an inner layer of densely pigmented cuboidal cells. The cells of the outermost layer are continuous with the cells of the inner layer. A narrow space lies between the outermost layer and the outer layer. The columnar cells in the outer layer contain well developed organelles but no pigment granules; they possess a basement membrane, lateral interdigitations, and junctional complexes near their apices. Numerous focal junctions and some ciliary channel-like structures were detected between the columnar cells of the outer layer and the cuboidal cells of the inner layer. The cuboidal cells of the inner layer are filled with pigment granules. These observations suggest that the columnar cells of the outer layer are nonpigmented epithelium, the cuboidal cells of the inner layer are pigmented epithelium, and the flattened cells in the outermost layer are derived from pigmented epithelium.
The invagination of the optic vesicle has, as one of its consequences, the apposition of the apices of the nonpigmented and pigmented epithelia of the ciliary processes of the eye. There are well developed intercellular ciliary "channels" formed at the apices of these cells. Embryologically the ciliary epithelia are homologous to the epithelia of the choroid plexus, a characteristically differentiated ependyma. These epithelial cells have a polarity. For example, the supranuclear region of the nonpigmented epithelia has Golgi apparatus. While stimulation of the epithelia of the choroid plexus by beta adrenergics or cholera toxin increases the rate of production of cerebrospinal fluid, similar stimulation of the adenylate complex within the ciliary epithelia decreases aqueous humor production. When the secretory function of the nonpigmented epithelial cell is activated, fluid is probably reabsorbed from the posterior chamber and secreted apically into the intercellular ciliary channels, in accord with cell polarity, thereby reducing net aqueous inflow. The fluid may enter the ciliary stroma thereafter and thus may become part of what may be called "uveal scleral" flow, or in this instance, uveal flow. The anatomy, physiology, and chemistry fit this hypothesis and form the basis for new investigations of a two-way transport across the ciliary epithelia.
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