Intracerebroventricular injection of TNF-alpha promotes sleep and is recovered in cervical lymph.
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Recent studies have shown that the central nervous system (CNS) communicates with the periphery by the drainage of cerebrospinal fluid and brain interstitial fluid into blood and lymph. We hypothesized that tumor necrosis factor (TNF)-alpha would not only influence the CNS by promoting sleep but also would be directly transmitted into the peripheral immune system. Five hundred nanograms of 125I-labeled TNF-alpha were injected into the lateral ventricles of the brain of six sheep and sampled in venous blood and cervical and prescapular lymph every 30 min for 6 h. 125I-TNF-alpha was measured in lymph nodes and control fat, skin, and muscle tissues 6 h postinjection. 125I-TNF-alpha was detected in the cervical lymphatics within the first 30 min and peaked within 2-3 h. 125I-TNF-alpha counts were elevated in the nodes of the head and neck region. Polysomnographic recordings of four animals showed that TNF-alpha induced a significant increase in slow-wave sleep at postinjection hours 4 and 5. CNS TNF-alpha and its direct drainage into the lymphatic system may influence both the sleeping/waking brain and peripheral immune functions. (+info)
Reconstitution of functional L-selectin ligands on a cultured human endothelial cell line by cotransfection of alpha1-->3 fucosyltransferase VII and newly cloned GlcNAcbeta:6-sulfotransferase cDNA.
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Recently, we proposed sialyl 6-sulfo Lewis X as a major carbohydrate-capping group of the L-selectin ligands on high endothelial venules in human lymph nodes. In this study we succeeded in reconstituting functional L-selectin ligands on a cultured human endothelial cell line, ECV304, by transfecting the alpha1-->3fucosyltranseferase VII (Fuc-T VII) and newly cloned GlcNAcbeta:6-sulfotransferase (6-Sul-T) cDNAs. The ECV304 cells transfected with Fuc-T VII cDNA expressed conventional sialyl Lewis X detected with specific antibodies including 2H5, whereas the cells transfected with 6-Sul-T cDNA expressed sialyl 6-sulfo lactosamine as well as MECA-79-defined carbohydrate determinants, but these singly transfected cells failed to express sialyl 6-sulfo Lewis X, as detected with the antisialyl 6-sulfo Lewis X mAb G152. Sialyl 6-sulfo Lewis X appeared only on the cells that were cotransfected with both 6-Sul-T and Fuc-T VII cDNAs. Significant adhesion of L-selectin-expressing cells was seen only to the doubly transfected ECV304 cells and was inhibited by G152. No adhesion was observed to the cells transfected either with 6-Sul-T or with Fuc-T VII cDNA alone. The mRNAs of the two enzymes were expressed or were inducible upon interleukin 1 stimulation in human endothelial cells. These results indicate that a set of carbohydrate determinants synthesized by the concerted action of the two enzymes, as typically represented by the sialyl 6-sulfo Lewis X-capping group, serves as an essential component of the ligand for L-selectin and that the reagents 2H5 and MECA-79, utilized in earlier studies to detect L-selectin ligand on high endothelial venules, recognize two different aspects of the same set of synthetic products. (+info)
Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma.
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Human herpesvirus 8 (HHV-8, also called KSHV) is linked to the etiopathogenesis of Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). The universal presence of HHV-8 in early KS has not yet been shown. We used a mAb (LN53) against latent nuclear antigen-1 (LNA-1) of HHV-8 encoded by ORF73 to study the distribution of the cell types latently infected by HHV-8 in patch, plaque, and nodular KS, MCD, and PEL. In early KS, HHV-8 is present in <10% of cells forming the walls of ectatic vessels. In nodular KS, HHV-8 is present in cells surrounding slit-like vessels and in >90% of spindle cells, but not in normal vascular endothelium. In addition, HHV-8 colocalizes with vascular endothelial growth factor receptor-3 (VEGFR-3), a marker of lymphatic and precursor endothelium. In early KS lesions, VEGFR-3 is more extensively expressed than LNA-1, indicating that HHV-8 is not inducing the proliferation of VEGFR-3-positive endothelium directly. In MCD, HHV-8 is present in mantle zone large immunoblastic B cells. No staining for LNA-1 is seen in samples from multiple myeloma, prostate cancer, and angiosarcoma, supporting the absence of any etiological link between these diseases and HHV-8. (+info)
TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1.
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An examination of thymocytes and peripheral T cells from SHP-1-deficient motheaten mice possessing a transgenic MHC class I-restricted TCR has implicated SHP-1 in regulating TCR signaling thresholds at three checkpoints in T cell development and activation. First, in the population of CD4-CD8- double negative thymocytes, SHP-1 appears capable of regulating signals from TCR complexes that control the maturation and proliferation of double negative thymocytes. Second, the loss of SHP-1 increased the number of CD4+CD8+ double positive thymocytes capable of maturing as TCRhigh single positive thymocytes. Third, the loss of SHP-1 altered the basal level of activation of naive lymph node T cells. Accordingly, SHP-1-deficient lymph node T cells bearing the transgenic TCR demonstrated a hyperresponsiveness to stimulation with cognate peptide. However, the loss of SHP-1 did not alter the cytolytic ability of mature effector cytotoxic T lymphocytes. Together these results suggest that SHP-1 contributes to establishing thresholds for TCR signaling in thymocytes and naive peripheral T cells. (+info)
The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells.
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Dendritic cell migration to secondary lymphoid tissues is critical for Ag presentation to T cells necessary to elicit an immune response. Despite the importance of dendritic cell trafficking in immunity, at present little is understood about the mechanisms that underlie this phenomenon. Using a novel transwell chemotaxis assay system, we demonstrate that the CC chemokine receptor-7 (CCR7) ligands 6Ckine and macrophage inflammatory protein (MIP)-3 beta are selective chemoattractants for MHC class IIhigh B7-2high bone marrow-derived dendritic cells at a potency 1000-fold higher than their known activity on naive T cells. Furthermore, these chemokines stimulate the chemotaxis of freshly isolated lymph node dendritic cells, as well as the egress of skin dendritic cells ex vivo. Because these chemokines are expressed in lymphoid organs and 6Ckine has been localized to high endothelial venules and lymphatic endothelium, we propose that they may play an important role in the homing of dendritic cells to lymphoid tissues. (+info)
Bystander virus infection prolongs activated T cell survival.
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In animals, T cells often die rapidly after activation, unless activation occurs in the presence of inflammatory factors. To understand how such activated cells survive to participate in immune responses, we studied the effects of viral infection on T cells responding to an unrelated superantigen. Normal T cells activated by superantigen in uninfected mice died as a result of their activation, whereas T cells that were activated during vaccinia infection survived longer in vivo and in culture. This bystander effect of viral infection on activated T cells was independent of effects on the magnitude of the initial T cell response, on induction of Bcl-2 and Bcl-x, on T cell proliferation, and on Fas killing. The failure of such effects to predict the fate of activated T cells in vivo indicates that virus infections shape T cell responses via mechanisms that differ from those described previously. These mechanisms may contribute to the ability of viral infections to induce autoimmunity. (+info)
Host B7-1 and B7-2 costimulatory molecules contribute to the eradication of B7-1-transfected P815 tumor cells via a CD8+ T cell-dependent mechanism.
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B7-1 (CD80)-transfected P815 tumor cells were previously shown to elicit tumor-eradicating immunity that leads to the regression of B7-1+ P815 tumors after transient growth in normal syngeneic (DBA/2) mice. Here, we show that not only the B7-1 molecule but also the B7-2 (CD86) molecule contributed to the eradication of B7-1+ P815 tumors. The B7-1 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed not only on the tumor cells but also on host APCs, including MAC-1+ cells. The B7-2 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed only on host APCs, such as B220+ cells, and not on the tumor cells. In spite of the fact that B7-expressing host APCs contributed to the eradication of B7-1+ P815 tumors, only CD8+ T cells without help from CD4+ T cells were important for tumor eradication. Taken together, these findings indicate that in addition to the ability of B7-1-transfected tumor cells to stimulate CD8+ T cell-mediated tumor-eradicating immunity directly, such tumor cells can also stimulate CD8+ T cell-mediated tumor-eradicating immunity indirectly as a result of cross-priming through B7-expressing host APCs. (+info)
Lessons learned from 500 cases of lymphatic mapping for breast cancer.
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OBJECTIVE: To evaluate the factors affecting the identification and accuracy of the sentinel node in breast cancer in a single institutional experience. SUMMARY BACKGROUND DATA: Few of the many published feasibility studies of lymphatic mapping for breast cancer have adequate numbers to assess in detail the factors affecting failed and falsely negative mapping procedures. METHODS: Five hundred consecutive sentinel lymph node biopsies were performed using isosulfan blue dye and technetium-labeled sulfur colloid. A planned conventional axillary dissection was performed in 104 cases. RESULTS: Sentinel nodes were identified in 458 of 492 (92%) evaluable cases. The mean number of sentinel nodes removed was 2.1. The sentinel node was successfully identified by blue dye in 80% (393/492), by isotope in 85% (419/492), and by the combination of blue dye and isotope in 93% (458/492) of patients. Success in locating the sentinel node was unrelated to tumor size, type, location, or multicentricity; the presence of lymphovascular invasion; histologic or nuclear grade; or a previous surgical biopsy. The false-negative rate of 10.6% (5/47) was calculated using only those 104 cases where a conventional axillary dissection was planned before surgery. CONCLUSIONS: Sentinel node biopsy in patients with early breast cancer is a safe and effective alternative to routine axillary dissection for patients with negative nodes. Because of a small but definite rate of false-negative results, this procedure is most valuable in patients with a low risk of axillary nodal metastases. Both blue dye and radioisotope should be used to maximize the yield and accuracy of successful localizations. (+info)