Distribution of two subtypes of receptors for endothelins in single smooth muscle cells isolated from guinea pig trachea.
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Animals↗
Biomedical subjects
A Ochi
Publications and source records attributed to A Ochi.
Effects of staphylococcal toxins on T-cell activity in vivo.
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Animals↗
Reduction of lupus nephritis in MRL/lpr mice by a bacterial superantigen treatment.
The effects of biweekly intravenous injections of Staphylococcus Enterotoxin B (SEB) into autoimmune MRL-lpr/lpr (MRL/lpr) mice were investigated. Rather than causing the expansion of V beta 8+ T cells, SEB administration resulted in the reduction V beta 8+, CD4-CD8- "double-negative" (DN) T cells. This was shown by FACS analysis as this putative pathogenic population was diminished in both spleen and lymph node. The symptoms of systemic lupus erythematosus (SLE) in MRL/lpr, which include high titers of anti-DNA antibodies and circulating immune complexes and proteinuria, were reduced in SEB-treated mice in a dose-dependent manner. The clinical parameters of SLE in MRL/lpr, which include lymph node hyperplasia and necrotic vasculitis, were suppressed in 50-micrograms SEB-treated mice. T cells bearing V beta 6 T cell receptor, which does not interact with SEB, were not reduced with SEB administration. Thus, disease suppression was associated with a specific reduction in the number of V beta 8+, DN T cells. These results implicate a possible therapeutic role of superantigen-based immunotherapy in V beta-restricted, T cell-dominated clinical syndromes.
Animals↗
Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B.
Clonal deletion and functional inactivation of self-reactive cells have been invoked as mechanisms underlying intrathymic development of T-cell tolerance. The relative importance of these mechanisms in the development of tolerance of more mature, peripheral T cells either to self or to exogenous antigens is unclear, although recent data relate the development of T-cell tolerance in the periphery to clonal anergy. We have now investigated the induction of extrathymic tolerance using BALB/c mice that were made tolerant to Staphylococcus aureus enterotoxin B, a superantigen which specifically interacts in such mice with T cells bearing V beta 8 antigen receptors. Both euthymic and athymic mice made tolerant to S. aureus enterotoxin B had a markedly reduced number of V beta 8.1,2+ CD4+ peripheral T cells. This reduction was accompanied by genomic DNA fragmentation that is associated with cell death. These results indicate that a deletional mechanism can contribute to the induction of T-cell tolerance in peripheral lymphoid cells.
Animals↗
Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice.
The cellular basis of the in vitro and in vivo T cell responses to Staphylococcus enterotoxin B (SEB) has been investigated. The proliferation and cytotoxicity of V beta 8.1,2+,CD4+ and CD8+ T cells were observed in in vitro response to SEB. In primary cytotoxicity assays, CD4+ T cells from control spleens were more active than their CD8+ counterparts, however, in cells derived from SEB-primed mice, CD8+ T cells were dominant in SEB-specific cytotoxicity. In vivo priming with SEB abrogated the response of V beta 8.1,2+,CD4+ T cells despite the fact that these cells exist in significant number. This SEB-specific anergy occurred only in V beta 8.1,2+,CD4+ T cells but not in CD8+ T cells. These findings indicate that the requirement for the induction of antigen-specific anergy is different between CD4+ and CD8+ T cells in post-thymic tolerance, and the existence of coanergic signals for the induction of T cell anergy is suggested.
Animals↗
Localization and characterization of endothelin receptors in human gliomas: a growth factor?
Localization and characterization of endothelin receptors in surgical specimens of human gliomas (6 benign astrocytomas and 7 glioblastomas multiforme) and in normal human cortices were studied using quantitative receptor autoradiographic methods. Low numbers of [125I]endothelin-1 [( 125I]ET-1) binding sites were detected in the gray matter of the human frontal cortex, with little binding in the white matter. Conversely, relatively high numbers of [125I]ET-1 binding sites were homogeneously present in tissue sections derived from astrocytomas, whereas higher numbers of [125I]ET-1 binding sites were heterogeneously located on groups of cells with a pseudopalisading appearance and pleomorphic astrocytes in glioblastoma multiforme. Necrotic areas within the tissue sections derived from glioblastoma were devoid of binding. Binding of [125I]ET-1 to gliomas and normal gray matter was specific. Unlabeled ET-1 and its natural analogs (ET-2 and ET-3) inhibited the binding of [125I]ET-1 to these lesions in a concentration-dependent manner and with similar high potencies. Possibly related substances, such as ion channel regulators (omega-conotoxin, apamin, and tetrodotoxin), a Ca2+ channel blocker (nicardipine), and growth factors (epidermal growth factor and insulin-like growth factor I), did not affect the binding to tissue sections derived from gliomas or from normal frontal cortices. Scatchard analysis revealed the presence of a single class and high-affinity binding sites for endothelin in normal cortex and in gliomas. There was no significant difference in the binding affinities: dissociation constants (Kd) were 2.1 +/- 0.5 nM in 6 astrocytomas, 2.5 +/- 0.4 nM in 7 glioblastomas, and 1.4 and 1.5 nM in two normal cortices.(ABSTRACT TRUNCATED AT 250 WORDS)
Binding Sites↗
Liposomes as carriers of cisplatin into the central nervous system--experiments with 9L gliomas in rats.
The anticancer agent cis-diamminedichloroplatinum (cisplatin) has several disadvantages, including extreme nephrotoxicity, rapid binding to plasma proteins, and poor penetration of the central nervous system. In this study liposomes, which can cross the blood-brain barrier, were investigated for their potential in delivering therapeutic agents to brain tumors. Liposomes prepared from egg phosphatidylcholine and cholesterol in a 3:1 molar ratio were divided into 1-ml aliquots and either labeled with 14C or treated with horseradish peroxidase (HRP). The preparations were administered via the carotid artery to rats bearing 9L glioma. Radioactive uptake by brain tumor and normal tissues was measured with a liquid scintillation counter. The presence of HRP-containing liposomes in capillary endothelium and brain tumor cells was demonstrated by light and electron microscopic histochemical techniques. Thirty minutes after injection of 14C-labeled liposomes, radioactive uptake was higher in the spleen than in normal brain, brain tumor, liver, and kidney. Also uptake was greater in brain tumor and lower in kidney than that of cisplatin given alone. Light microscopy showed HRP-containing liposomes in brain tumor tissue 30 minutes after injection. On electron microscopy, liposomes were found to be regularly distributed in surface invaginations and vesicles of capillary endothelial cells. They were also observed within tumor cells. These results indicate that liposomes can penetrate the blood-brain barrier and hold promise as drug carriers in the treatment of brain tumors with cisplatin.
Animals↗
[A rare case of congenital tricuspid stenosis treated with modified Fontan operation].
A rare case of congenital tricuspid stenosis treated with modified Fontan operation was reported. The patient was 13 years old boy and his chief complaint was cyanosis. Cyanosis appeared in his neonatal period and squatting developed in his childhood. He underwent Blalock's shunt operation at 5 years of age. His exercise tolerance was limited at the admission for the radical operation. Angiocardiography showed the annular stenosis of tricuspid valve and the moderate hypoplasia of right ventricle. The right ventricular volume was 56 ml (equivalent to 35% of the normally expected right ventricular volume) and the diameter of tricuspid annulus was 13 mm (equivalent to 58% of the normally expected diameter). Atrial septal defect was associated with but pulmonary stenosis did not exist. His left ventricular function was good and pulmonary vascular resistance was not raised. A diagnosis of tricuspid stenosis was made and Fontan's repair was considered to be possible for his correction. Operative findings showed normal architecture of tricuspid valve with the three leaflets but tricuspid annulus was narrow. Tricuspid valve stenosis was considered to be caused by the hypoplasia of tricuspid ring and surgical dilatation was found to be difficult. Therefore, modified Fontan operation (RA-RV connection) was performed. His cyanosis disappeared and exercise tolerance was improved after the operation. Cardiac catheterization and angiocardiography were performed 8 months and 28 months after the operation. His righ ventricular volume was increased to 123 ml (equivalent to 57% of the normally expected volume) followed by RA-RV connection.
Adolescent↗
[Ultrastructure of capillary permeability in human brain tumor: disseminated and metastatic medulloblastoma].
The ultrastructure of the tumor vessels of primary cerebellar, subarachnoidal disseminated and extraneural metastatic medulloblastomas was studied. They were compared with those in glial, nonglial and metastatic brain tumors which have been previously reported. Twelve surgical specimens were examined. Seven tumors were limited to the vermis, the floor of the fourth ventricle and the cerebellar hemispheres. Four gross nodule seedings were demonstrated in the cerebral and spinal subarachnoid space. One metastasis was demonstrated in the subclavicular lymph node. Ultrathin section of those tumors and replica specimens were studied under the transmission electron microscope. The tumor vessels of primary medulloblastoma and glial tumors had nonfenestrated capillaries and were morphologically similar to normal brain capillaries. On the other hand, the tumor vessels of disseminated and metastatic medulloblastoma, nonglial tumors, and metastatic brain tumors had fenestrated capillaries. These findings were anticipated because the arachnoid membrane and lymph nodes have fenestrated capillaries. The presence of fenestration suggests that the tumor vessels of disseminated and metastatic brain tumors resemble the blood vessels found in normal arachnoid membrane and lymph nodes.
Adult↗
[Ultrastructure of capillary permeability in human brain tumor: primary meningeal malignant melanoma].
The tumor vessels of a primary meningeal malignant melanoma were studied by electron microscopy. There were numerous endothelial fenestrae and basal lamina abnormalities in the intrinsic tumor capillaries. They resembled the tumor vessels found in nonglial tumors, but were distinctly different from those seen in glial tumors with nonfenestrated capillaries. These findings were anticipated because leptomeninges have fenestrated capillaries.
Basement Membrane↗
The targeting of CD4+ T lymphocytes to a B cell lymphoma. A comparison of anti-CD3-anti-idiotype antibody conjugates and antigen-anti-idiotype antibody conjugates.
We have targeted CD4+ cytotoxic Th (Th/c) lymphocytes to a B cell lymphoma, through the use of a bispecific antibody containing binding sites for both the CD3 complex on the Th/c and the Id on the surface Ig of the B lymphoma (anti-CD3-anti-Id). Cloned, keyhole limpet hemocyanin (KLH)-specific Th/c cells were nonspecifically activated by the anti-CD3-anti-Id conjugate to lyse the Id+ B lymphoma A20-HL. This cytotoxicity was not inhibited by antibodies to CD4 or LFA-1 alpha molecules. The anti-CD3-anti-Id conjugates also induced non-lytic Th clones to become cytotoxic, a function not elicited when these cells were activated specifically by Ag. We compare this model to our previously described system where we targeted the KLH-specific Th/c cells to the Id+ B lymphoma A20-HL via a conjugate consisting of KLH covalently linked to the anti-Id antibody (KLH-anti-Id). The mechanism involved processing and presentation of KLH by the A20-HL target. This Ag-specific cytotoxicity was MHC class II restricted and was inhibited by antibodies to the CD4 molecule. In both systems, activation of the Th/c cells resulted in bystander killing of tumor but not normal targets. These results may have important implications for the use of Th/c cells in tumor immunotherapy.
Animals↗
Evidence for an involvement of T4+ cytotoxic T cells in tumor immunity.
Cell-mediated immunity against cancer cells primarily involves class I major histocompatibility complex (MHC)-restricted cytotoxic T cells and natural killer (NK) cells. To investigate whether T4+ cytotoxic T cells also have a role in tumor-specific immunity, mice were immunized with a B cell lymphoma. T cell hybridomas were constructed from the immune spleen cells and analyzed for their cytotoxic ability against the immunizing lymphoma. A T4+, Lyt-1+ hybridoma cell line was developed (103L2) which specifically killed the immunizing tumor cells but not normal B cells or a range of other tumor cells of B or non-B origin. This cytotoxic hybridoma cell line differed from Lyt-2+ cytotoxic T lymphocyte cells and NK cells, commonly identified with cytotoxicity, in a number of important ways. First, the cells were class II MHC restricted; second, interleukin-2 was released from activated effector cells; and finally but most importantly, innocent nonparticipating bystander cells were also killed. The significance of this observation was that normal cells were protected, although a broad range of tumor cell types, including tumor antigen-negative mutants, were killed. It is therefore conceivable that T4+ cytotoxic T cells might play an important role in tumor immunity through the direct recognition and lysis of tumor cells while any tumor variants, arising due to antigen loss, would remain susceptible through the bystander killing effect and normal cells would remain unaffected. These results strongly suggest that tumor-reactive T4+ cytotoxic T cells belong to a new category of effector cells with an important role in tumor-specific immunity.
Animals↗
[Expression of insulin-like growth factor I receptors in human brain tumors: comparison with epidermal growth factor receptor by using quantitative autoradiography].
By using quantitative autoradiographic techniques, receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) were analyzed in 13 samples of human brain tumors (4 low grade astrocytomas, 7 glioblastomas, 1 anaplastic ependymoma and 1 medulloblastoma). High number of specific binding sites for IGF-I and EGF were homogeneously present in tissue sections derived from glioblastoma. In low grade astrocytoma, relatively high numbers of binding site for EGF were observed, but there was no significant difference in concentrations of IGF-I binding sites between tumors and control cortex. In medulloblastoma, only IGF-I binding sites were present. These observations might indicate that both IGF-I and EGF are involved in the growth modulation of human gliomas possibly through paracrine or autocrine mechanisms. Antagonists to growth factors or monoclonal antibody against those receptors could have the way for therapeutic application for gliomas.
Astrocytoma↗
[Expression of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) receptors in primary non-glial human brain tumors].
The expression of IGF-I and EGF receptors in the primary non-glial brain tumors (8 meningiomas, 2 neurinomas, 1 hemangioblastoma, 2 primary malignant lymphomas) was analyzed by using in vitro quantitative autoradiographic techniques. Specific binding sites for IGF-I were co-localized with those for EGF in the meningiomas and the hemangioblastoma examined. However, in the neurinomas and the malignant lymphomas, only IGF-I binding sites were present. In addition, IGF-I and EGF synergistically increased 3H-thymidine incorporation into DNA synthesis by the primary cultured meningioma cells, in dose-dependent manner. These observations can be interpreted to mean that both IGF-I and EGF may exist as autocrine or paracrine peptides involved in the growth not only of glioma but also of non-glial brain tumors.
Adult↗
[Ultrastructure of capillary permeability in malignant lymphoma].
The ultrastructure of the blood vessels of primary central nervous system malignant lymphoma was studied and compared with those in glial, non-glial and metastatic brain tumors. Five surgical specimens were studied by conventional ultrathin section and freeze-fracture replica techniques. Tumor vessels of various sizes were found. The luminal surfaces of the tumor vessels were irregular and the basal lamina had multiple-layer structure. The perivascular spaces were enlarged and infiltrated with tumor cells. The endothelium had marked infoldings, increased pinocytotic vesicles and fenestrations. The intercellular junctions were short but no obvious opening was seen. On the replica specimen pinocytotic vesicles were calculated on an average of 28 per microns2. The essential features of the blood vessels in primary central nervous system malignant lymphoma were the fenestrated vessels. They resembled the blood vessels found in non-glial and metastatic brain tumors, but were distinctly different from those seen in glial tumors with non-fenestrated vessels.
Adult↗
Resistance of multidrug-resistant lines to natural killer-like cell-mediated cytotoxicity.
Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK-mediated cytotoxicity. Studies with two independently selected multidrug-resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK-mediated cytotoxicity and increased levels of membrane P-glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK-mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.
Cell Line↗
A novel strategy for immunotherapy using antibody-coupled carriers to focus cytotoxic T helper cells.
Targeting of cytotoxic T cells to cell-bound antigens has previously been reported using bispecific antibodies. In this report we document a novel targeting system whereby cytotoxic T helper (Thc) cells were targeted to a B cell lymphoma by means of an anti-idiotypic antibody (anti-Id), specific for the surface immunoglobulin of the B cell, coupled to the carrier protein keyhole limpet hemocyanin (KLH). In this system the anti-Id-KLH complex bound to the Id determinant of the surface immunoglobulin of the B cell lymphoma. This complex was then presented in a major histocompatibility complex class II-restricted manner to the KLH-specific Thc cell (KLH55) which was induced into its cytolytic pathway through the specific recognition of KLH. The uniqueness of this system was that it utilized the inherent ability of the target B cell to process and present antigen. This offered the distinct advantage that processed antigen re-expressed on the cell membrane was in a more stable form, thereby enabling the target cell to remain susceptible to cytotoxicity for an extended period of time. Furthermore, as is characteristic of Thc cells in general, bystander killing was demonstrated and Id (or Ia)-negative mutants of the target cell did not escape destruction. The adaptation of such a system will have useful implication for future immunotherapeutic strategies.
Animals↗
Clonal analysis of antigen-specific interactions between T cells and genetically engineered B cells.
In order to investigate T cell-B cell interactions we constructed monoclonal, antigen-specific T- and B-cell populations. The Ia+ B-cell lymphoma A20-2J was transfected with trinitrophenyl (TNP)-specific heavy (mu) and light (kappa) chain Ig genes. A hapten-carrier complex (TNP-keyhole limpet hemocyanin (KLH)) bound to the surface Ig expressed on the transfectant and was presented to carrier-specific T-cell hybridoma clones at markedly low doses of antigen (0.01 microgram/ml) and in an Ia-restricted fashion. Two responses were elicited in the responding T-cell clones: (i) high levels of IL-2 secretion (320 units/ml), and (ii) cytotoxicity directed against the antigen-presenting B cell. This cytotoxicity was inhibited by D-mannose and was directed against innocent bystander cells, unlike cytotoxicity mediated by NK cells or alloreactive cytotoxic T lymphocyte. Helper and cytotoxic functions were often present in different T-cell hybridomas but some clones exhibited both activities. One representative T-cell hybridoma exhibited strong helper function for TNP-primed splenic B cells as detected in a plaque-forming cell assay, but was cytotoxic toward antigen-presenting B cells. Such monoclonal assay systems for studying cognate interactions of heterogeneous T cells and specific antigen-presenting cells will provide us with valuable new approaches for the study of antigen-specific T-cell regulation of B-cell activation in immune responses.
Animals↗