Cross-presentation of tumour antigens: evaluation of threshold, duration, distribution and regulation.
(25/803)
The development of technology to measure antigen presentation in the secondary lymphoid system has provided the opportunity of analysing components of the host antitumour immune response that have, until now, been unavailable for study. In particular, this technology has enabled us to evaluate threshold levels of tumour antigen required for cross-presentation in draining lymph nodes, the duration of this antigen presentation and processes that regulate tumour antigen presentation. Thus, we have been able to dissect out the relationship between antigen presentation and the resultant development of effector function in class I-restricted T cells, as well as the role of regulatory CD4 cells. We have also used this technology to evaluate the effects of antitumour therapy on local antigen cross-presentation. (+info)
Flow reduces the amplitude and increases the frequency of lymphatic vasomotion: role of endothelial prostanoids.
(26/803)
Fluid dynamic forces have substantial effects on the movement of lymph and activity of lymph vessels. The effect of increases in intraluminal flow on spontaneous pumping activity of isolated collecting lymphatics has not yet been characterized in a condition in which the intraluminal pressure is constant. Thus, in afferent lymph microvessels isolated from rat iliac lymph nodes, changes in maximum (Dmax) and minimum (Dmin) diameter to increases in perfusate flow were investigated in the presence of a constant perfusion pressure of 6 cmH2O. Intraluminal flow was elicited by increases in the difference between outflow and inflow pressures (Pdiff, from 0 to 6 cmH2O). Diameters were measured by videomicroscopy. In response to increases in perfusate flow, Dmax and Dmin of lymphatics decreased from 157.5 +/- 6.1 to 90.9 +/- 5.6 micron and from 91.9 +/- 5.3 to 66.3 +/- 3.6 micron, respectively, whereas vasomotion frequency increased from 18.0 +/- 0.7 min(-1) to 23.4 +/- 1.1 min(-1) (at Pdiff of 4 cmH2O). Removal of extracellular Ca2+ abolished spontaneous diameter oscillations; under these conditions the passive diameter of lymphatics was 216.0 +/- 7.1 micron and did not change in response to increases in perfusion. In the absence of endothelium, flow-induced changes in Dmax, Dmin, and oscillation frequency were eliminated. Nomega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, did not affect flow-induced changes in diameter of lymphatics. In contrast, indomethacin, an inhibitor of prostaglandin synthesis, or SQ-29,548, a PGH2/thromboxane A2 (PGH2/TxA2) receptor blocker, inhibited the perfusion-induced reduction of Dmax and Dmin of lymphatics and also the increase in the frequency of vasomotion. These findings suggest that the sensitivity of lymphatic endothelium to increases in intraluminal flow could provide an important local intrinsic mechanism for the control of lymphatic resistance by release of constrictor prostanoids PGH2/TxA2. (+info)
Relationship between intracranial pressure and cervical lymphatic pressure and flow rates in sheep.
(27/803)
Previous reports from our group demonstrated that about one-half of the total volume of cerebrospinal fluid (CSF) removed from the cranial vault in sheep is transported into extracranial lymphatics, especially cervical lymphatic vessels in the neck. In this study, we tested the hypothesis that an elevation of intracranial pressure (ICP) would increase cervical lymphatic pressure and lymph flow rates in anesthetized sheep. Catheters were inserted into both lateral ventricles, the cisterna magna, cervical lymphatics, and the jugular vein. A ventriculo-cisternal perfusion system was employed to regulate ICP. Mean (P = 0.008), peak (P = 0.007), and baseline (P = 0.013) cervical lymphatic pressures increased as ICP was elevated from 10 to 70 cmH2O in 20-cmH2O increments. Similarly, cervical lymph flow rates increased (P < 0.001), with flows at 70 cmH2O ICP observed to be approximately fourfold higher than those at 10 cmH2O ICP. No changes were observed in mesenteric lymph flow rates (vessels not expected to drain CSF). We conclude that cervical lymphatic vessels play an important role in the transport of CSF from the cranial vault when ICP is elevated. (+info)
Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model.
(28/803)
Human granulocytic ehrlichiosis (HGE) results in fever, pancytopenia, and mild liver injury. We used a mouse model to examine immunity in the pathogenesis of HGE. HGE agent-infected C3H/HeJ mice were necropsied over 21 days. Histologic, immunohistologic, and serologic analyses, blood culture, tissue and blood polymerase chain reaction (PCR), cell counts, serum chemistries, and plasma cytokine ELISAs were performed. No clinical signs were detected. Ehrlichiae were identified in neutrophils in hematopoietic tissues maximally on day 7. Interleukin (IL)-10 levels were high throughout, whereas interferon (IFN)-gamma levels peaked on days 7 and 10 and dropped thereafter. Hepatic lymphohistiocytic aggregates with apoptoses were maximal at day 14. HGE-agent infection of mice induces pathologic changes similar to those in infected humans, despite differences in cytokine profile. The IFN-gamma peak prior to maximal pathologic change, when ehrlichiae are absent in tissues, suggests a role for host immunity in the pathogenesis of HGE. (+info)
Lymphatic dissemination and comparative pathology of recombinant measles viruses in genetically modified mice.
(29/803)
The dissemination of the Edmonston measles virus (Ed-MV) vaccine strain was studied with genetically modified mice defective for the alpha/beta interferon receptor and expressing human CD46 with human-like tissue specificity and efficiency. A few days after intranasal infection, macrophages expressing Ed-MV RNA were detected in the lungs, in draining lymph nodes, and in the thymus. In lymph nodes, large syncytia which stained positive for viral RNA and for macrophage surface marker proteins were found and apoptotic cell death was monitored. In the thymus, smaller syncytia which stained positive for macrophage and dendritic cell markers were detected. Thus, macrophages appear to be the main vectors for dissemination of MV infection in these mice; human macrophages may have a similar function in the natural host. We then compared the pathogenicities of two recombinant viruses lacking the C or V nonstructural proteins to that of the parental strain, Ed-MV. These viruses were less effective in spreading through the lymphatic system and, unlike Ed-MV, were not detected in the liver. After intracerebral inoculation the recombinant viruses caused lethal disease less often than Ed-MV and induced distinctive patterns of gliosis and inflammation. Ed-MV was reisolated from brain tissue, but its derivatives were not. C- and V-defective viruses should be considered as more-attenuated MV vaccine candidates. (+info)
Lymphangioblasts in the avian wing bud.
(30/803)
The development of the lymphatics has not yet been studied experimentally. Descriptive studies could not answer the question whether the lymphatics are exclusively derived by sprouts of the early embryonic lymph sacs, or whether lymphangioblasts in the mesenchyme contribute to the lymphatic system. We have studied the development of the lymphatics in quail-chick chimeras. In 6.5-day-old quail embryos, the endothelium of the jugulo-axillary lymph sac can be demonstrated with the QH1 antibody. In contrast to the jugular vein and the aorta, the lymph sac is irregularly shaped and does not possess a media of smooth muscle cells, and, the lymph sac endothelium starts to express the vascular endothelial growth factor receptor-3 (VEGFR-3). Cells of the quail paraxial mesoderm grafted into chick embryos integrate into the endothelium of the jugular lymph sac, strongly indicating the existence of lymphangioblasts. In the wing of 10-day-old quail embryos, VEGFR-3-positive lymphatics are accompanying all major blood vascular routes. On day 3.5 of development, that is about one day before the first occurrence of the jugulo-axillary lymph sac, we grafted distal wing buds of chick embryos homotopically into quail embryos. The chimeric wings were analyzed on day 10. The VEGFR-3 and QH1 double staining revealed that the lymphatics were formed by both chick and quail endothelial cells. This result shows that the lymphatics of the wing do not exclusively develop from sprouts of the lymph sacs, but also by recruitment of local lymphangioblasts. (+info)
Postprandial hyperlipidemia in streptozotocin-induced diabetic rats is due to abnormal increase in intestinal acyl coenzyme A:cholesterol acyltransferase activity.
(31/803)
Postprandial hyperlipidemia (PH) is recognized as a significant risk factor for cardiovascular disease. The present study, involving rats with streptozotocin (STZ)-induced diabetes, was performed to establish a PH model and to examine the relation between small intestinal acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity and serum lipid levels in the postprandial state. The small intestinal ACAT activities in normal rats during the experimental period were 4 to 5 pmol/mg protein per minute. In contrast, in the diabetic rats, the ACAT activities were 2 to 3 times higher than activities seen in normal rats from 7 to 21 days after the STZ injection in the absence of a high fat diet and hyperplasia in the gut. In an oral fat-loading test that used diabetic rats that had been injected with STZ (60 mg/kg) intravenously 14 days previously, the postloading changes in the serum concentrations of total cholesterol (TC) and triglyceride (TG) were significantly greater in the diabetic rats than in normal rats. Single oral administration of (1s,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane- 1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate (F-1394, 3 to 30 mg/kg), a potent ACAT inhibitor, suppressed the post-fat-loading elevation of serum TC levels in the diabetic rats in a dose-dependent manner without affecting serum glucose levels. Furthermore, the small intestinal ACAT activity, serum TG levels, and lymphatic absorption of TC and TG in the rats that were administered F-1394 (30 mg/kg) were reduced by approximately 90%, 70%, 30%, and 15%, respectively. This is the first evidence that elevated ACAT activity in the gut, unlike hyperplasia and hyperphagia, induces PH in rats. Our results strongly suggest that F-1394 may be a potential treatment for PH in humans. (+info)
Immunological activation of dermal Langerhans cells in contact with lymphocytes in a model of human inflamed skin.
(32/803)
Langerhans cells play an important role in the skin's immune system. Little is known, however, about the antigen-presenting capacity of Langerhans cells in the context of skin inflammation. By immunohistochemistry we investigated the phenotypic characteristics of epidermal and dermal Langerhans cells and their spatial relationship with infiltrating lymphocytes. We studied skin flaps autotransplanted to the oral cavity to fill a defect after maxillofacial cancer surgery. In 15 of 21 cases sampled for the present study, the skin flaps were severely inflamed by Candida albicans infection. In contrast to the normal skin, such inflamed skin showed a marked increase in CD1a(+) dermal Langerhans cells. Double immunohistochemistry revealed that dermal Langerhans cells abundantly expressed B7-2 (CD86), a representative costimulatory molecule, and CD83, a marker of mature dendritic cells. Furthermore, these dermal Langerhans cells were in close contact with CD4(+)/CD45RO(+) lymphocytes. This cell-to-cell contact was further visualized by immunoelectron microscopy. Langerhans cells were also observed within lymphatic vessels that were identified by the expression of vascular endothelial growth factor receptor-3. Ki-67 labeling indices were 4.2% in CD4(+) T cells and 0.8% in CD8(+) T cells within the dermis. Factor XIIIa(+) dermal dendrocytes were distributed outside the clusters of lymphocytes and were not in contact with them. Our observations indicate that dermal Langerhans cells in the inflamed skin are activated to express common phenotypes to mature dendritic cells so that they could stimulate neighboring memory CD4(+) T cells. (+info)