Remnant-like particles and restenosis of coronary arteries after PTCA.
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Angioplasty, Balloon, Coronary↗
Biomedical subjects
K Yui
Publications and source records attributed to K Yui.
Comparison of behavioural effects of repeated treatment with methamphetamine plus scopolamine and methamphetamine alone on behavioural sensitization and conditioned response.
We investigated how repeated treatments with methamphetamine (4.0 mg kg-1, i.p.) plus scopolamine (0.5 mg kg-1, i.p.) and methamphetamine alone effected behavioural sensitization and conditioned response in rats. Repeated methamphetamine plus scopolamine treatment induced a more progressive and enduring enhancement of focused stereotyped behaviour than repeated methamphetamine treatment. Stereotyped behaviour induced by methamphetamine plus scopolamine was reproduced by challenge injections of methamphetamine plus scopolamine, methamphetamine, and to a lesser extent by scopolamine challenges. The methamphetamine plus scopolamine-sensitized rats were conditioned to a low frequency tone (300 Hz, 100 dB) associated with the drug state. They exhibited a conditioned response to pairings of the tone (conditioned stimulus) and placebo injections. However, they did not respond to the tone alone or the placebo injections alone. The methamphetamine-sensitized rats failed to demonstrate any conditioning; only the repeated methamphetamine plus scopolamine treatment induced sensitization to the drug-associated tone. Pairings of exteroceptive conditioned stimulus-interoceptive unconditioned stimulus associations may provide an important source for conditioning to the tone associated with the drug state. We conclude that behavioural sensitization may operate via a reciprocal balance between the dopaminergic and cholinergic inhibitory systems, in favour of a dopaminergic dominance. Conditioning to the drug-associated tone may be mediated via a reciprocal balance between the two transmitter systems.
Animals↗
Spontaneous recurrence of methamphetamine psychosis: process and monoamine neurotransmitter function.
We studied the process that causes a spontaneous recurrence of methamphetamine (MAP) psychosis, a phenomenon known as flashbacks, in 41 female flashbackers by a comparison of clinical characteristics between the 41 flashbackers and 87 non-flashbackers with previous MAP psychosis. We evaluated plasma levels of monoamine metabolites in 25 of the 41 flashbackers, 19 of the 87 non-flashbackers, 9 female patients with persistent MAP psychosis and 61 physically healthy female controls. All 41 flashbackers had experienced a significantly greater frequency of threatening events and threatening paranoid-hallucinatory states than the 87 non-flashbackers during previous MAP abuse. The triggering factor was a mild fear of other persons due to the evocation of frightening images, encoded through threatening experiences during previous MAP abuse. Norepinephrine (NE) levels were significantly associated with a history of flashbacks. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were significantly higher during flashbacks and during periods of normalcy in the flashbackers, and in the non-flashbackers, than MHPG levels in the user controls. NE levels in the patients with persistent MAP psychosis were also significantly higher than NE levels in the user controls. Elevated NE levels in the flashbackers were associated with disrupted NE, 5-HT and DA turnover. Thus, MAP-induced sensitization to frightening images may have caused the flashbacks due to aggravated noradrenergic hyperactivity.
Adult↗
Delayed allograft rejection by T cell receptor V beta 8.1 transgenic mice peripherally tolerized to Mls-1.
One commonly studied model system for peripheral tolerance is the antigen-specific unresponsiveness of T cells from mice previously inoculated with superantigens such as Mls-1a. In this study, we used a TcR V beta 8.1 transgenic mouse model to investigate whether mice peripherally tolerized to Mls-1a exhibit delayed skin allograft rejection. We report dramatic prolongation of skin allograft survival in V beta 8.1 transgenic but not in non-transgenic mice tolerized to Mls-1a. Peripherally induced unresponsiveness to Mls-1a can, therefore, be considered true tolerance.
Animals↗
Gld and lpr mice: single gene mutant models for failed self tolerance.
Mice homozygous for the gld or lpr mutations develop autoimmunity, and a lymphoproliferative disorder involving accumulation of huge numbers of unusual CD4-CD8-TCR alpha beta lo T cells. Here we review our past work with gld mice, and attempt to explain lymphoproliferation in terms of current models of T cell maturation and self-tolerance induction. The availability of molecular probes to the gene products of lpr and gld should shortly lead to a better understanding of the acquisition of self tolerance during T cell maturation and of autoimmunity.
Animals↗
Stereotyped behavioral responses to an auditory stimulus in the course of repeated treatment with methamphetamine plus scopolamine and methamphetamine in rats.
The present experiment was designed to study the effects of an auditory stimulus with 300 Hz, 100 dB on gradual emergence of behavioral sensitization in the course of repeated administration of methamphetamine (MAP) in combination with scopolamine (SCOP) and MAP. Repeated intraperitoneal injection of MAP (4.0 mg/kg) plus SCOP (0.5 mg/kg) induced significantly progressive and enduring enhancement of stereotyped behavior, resulting in intense, focussed stereotypy intermingled with gnawing and licking compared to repeated MAP treatment. Vigorous stereotyped behavior induced by repeated MAP plus SCOP was progressively attenuated by the tone, resulting in attenuation of the development of behavioral sensitization. Conversely, the tone had no invariable effects on behavioral sensitization induced by repeated MAP treatment. The present findings indicate that repeated MAP plus SCOP treatment progressively induced attenuating effects of tone as low as 300 Hz on MAP plus SCOP-induced intense stereotypy and vigorous behavioral sensitization. These findings suggest that a reciprocal balance between dopaminergic and cholinergic inhibitory systems may be involved in producing behavioral sensitization, and in the attenuating effects of the tone on MAP plus SCOP-induced vigorous behavioral sensitization.
Acoustic Stimulation↗
Two separate mechanisms of T cell clonal anergy to Mls-1.
T cell tolerance to superantigen can be mediated by clonal anergy in which Ag-specific mature T cells are physically present but are not able to mount an immune response. We induced T cell unresponsiveness to minor lymphocyte stimulations locus antigen (Mls)-1a in mice transgenic for TCR V beta 8.1 in three different systems: 1) injection of Mls-1a spleen cells, 2) mating with Mls-1a mice, and 3) bone marrow (BM) chimeras in which Mls-1a is present only on nonhematopoietic cells. CD4+8-V beta 8.1+ cells from all these groups did not proliferate in response to irradiated spleen cells from Mls-1a mice. We compared the response of these cells by T cell/stimulator cell conjugate formation, Ca2+ mobilization, and proliferation assays. The mechanisms underlying the unresponsiveness of these T cells appear to differ. CD4+8-V beta 8.1+ cells from Mls-1a spleen cell-injected mice mobilized cytoplasmic Ca2+ but proliferated at a reduced level in response to cross-linking with anti-TCR mAb. However, these cells formed conjugates, mobilized Ca2+, and proliferated in response to Mls-1a when activated B cells were used as stimulators, although they produced reduced levels of IL-2. In Mls-1a/b V beta 8.1 transgenic mice, a subset in CD4+8-V beta 8.1+ cells did not mobilize cytoplasmic Ca2+ after TCR cross-linking. Their conjugate formation, Ca2+ mobilization, or proliferation in response to Mls-1a on activated B cells was undetectable. Finally, CD4+8-V beta 8.1+ cells from the BM chimeras proliferated to TCR cross-linking at a partially reduced level and formed conjugates, mobilized Ca2+, and proliferated in response to Mls-1a on activated B cells. These features suggest that the mechanisms underlying the maintenance of anergy in Mls-1a spleen cell-injected mice are distinct from those in Mls-1a mice.
Animals↗
Reduced CD3-mediated protein tyrosine phosphorylation in anergic CD4+ and CD8+ T cells.
Mice inoculated i.v. with superantigens exhibit long lived Ag-specific T cell tolerance. An in vitro model for this phenomenon is the ensuing unresponsiveness of Th1 T cell clones activated via the TCR/CD3 complex in the absence of co-stimulation. We have previously demonstrated alterations in TCR-mediated early protein tyrosine phosphorylation events in Th1 clones anergic for IL-2 production. In this study, we demonstrate unresponsiveness in CD4+ and CD8+ T cells from V beta 8.1 transgenic mice inoculated i.v. with the superantigen Mls-1a. The unresponsiveness of both CD4+ and CD8+ T cells involves defective IL-2 production upon restimulation, with CD4+ T cells exhibiting an additional defect in IL-2 utilization. The transgenic model allowed study of T cell signaling in a relatively homogeneous population of unresponsive cells without elaborate purification of Ag-reactive populations. Both CD4+ and CD8+ T cells exhibit altered tyrosine phosphorylation of two protein substrates upon CD3-mediated restimulation. The substrates involved, p38 and p75, are of identical size to substrates similarly affected in anergic Th1 clones. Altered tyrosine phosphorylation is therefore closely associated with defective IL-2 production in these three anergic T cell types, and may play a role in the maintenance of anergy.
Animals↗
Frequent deletion of the transgene in T cell receptor beta chain transgenic mice.
TCR V beta 8.1 transgenic mice were generated using a genomic TCR V beta gene construct under the control of its promoter and enhancer. Among three lines of transgenic mice, one line expressed the transgenic TCR on only approximately 70% of peripheral T cells, while the other two lines expressed it on almost all mature T cells. T cells which lacked expression of the transgenic TCR beta chain expressed endogenous TCR beta chains. The molecular basis underlying the lack of transgene expression in T cells of this line of transgenic mice was investigated. The transgenic TCR- cells were isolated by two methods. First, Thy-1+ V beta 8.1/8.2- cells were purified from peripheral T cells using cell sorting. Second, transgenic TCR- T cell clones were established. In both cases, Southern blotting indicated that V beta 8.1- T cells had deleted the transgenic TCR gene. Thus, deletion of the transgenic TCR can occur in a high proportion of T cells, which allows rearrangement and expression of endogenous TCR beta chains.
Animals↗
T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection.
Shaping of the T cell repertoire by selection during intrathymic maturation involves T cell receptor (TCR) recognition of major histocompatibility complex/self-antigen complexes. In this communication, we studied the ability of minor lymphocyte stimulating (Mls) determinants to act as self-tolerogens in the selection of the T cell repertoire. We demonstrate that unprimed T cells from normal as well as TCR transgenic mice form Mls-specific conjugates with antigen-presenting cells, and that this TCR-ligand interaction leads to elevation of intercellular Ca2+ ([Ca2+]i). Peripheral T cells from TCR transgenic mice expressing receptors specific for self-Mls antigen show no reactivities to Mlsa. However, a proportion of immature thymocytes from these mice show specific binding and strong [Ca2+]i elevation in response to self-antigen-presenting cells, although these thymocytes do not proliferate. This self-reactivity of thymocytes is inhibited by antibodies specific for TCR, CD4, CD8, class II molecules, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. These results demonstrate for the first time that before thymic negative selection, immature T cells can specifically interact with cells bearing self-antigen, and suggest that the resulting TCR-dependent signal transduction events provide a basis for negative selection of self-reactive T cells.
Animals↗
Inhibition of abnormal T cell development and autoimmunity in gld mice by transgenic T cell receptor beta chain.
Mice homozygous for the gld (generalized lymphoproliferative disease) mutation developed systemic autoimmune disease and severe lymphadenopathy due to an age-related accumulation in the peripheral lymphoid organs of polyclonal T cells bearing a unique phenotype (CD4-CD8-TCR alpha beta+B220+). These T cells overexpress T cell receptor (TcR) alpha beta chain RNA, proto-oncogenes c-myb and fyn, and proliferate poorly in response to TcR-mediated stimulation. The origin of these T cells is poorly understood. To study the influence of a functionally rearranged TcR beta chain on the T cell developmental abnormality of the gld mutation and autoimmunity, we have backcrossed TcR V beta 8.1-transgenic mice to C3H-gld/gld to homozygosity (transgenic gld mice). In transgenic gld mice, lymphadenopathy was markedly inhibited and the accumulation of CD4-CD8- T cells did not occur, although the remaining T cells overexpressed c-myb and proliferated poorly in response to TcR occupancy. These features indicate that the pattern of proto-oncogene expression and abnormal function persist in phenotypically normal T cells in transgenic gld mice, and that these characteristics can be dissociated from the accumulation of CD4-CD8- T cells. The hypergammaglobulinemia and anti-double-stranded DNA (anti-dsDNA) antibody production was partially improved in transgenic gld mice, supporting the critical role of T cells in abnormal B cell activation described in autoimmunity-prone mice. To investigate further the mechanisms underlying the inhibition of CD4-CD8- T cell accumulation in transgenic gld mice, the fetal ontogeny of T cells in transgenic mice was compared with that of non-transgenic mice. In transgenic thymus, development of TcR alpha beta+ cells was accelerated as detected by earlier expression of CD4, CD8 and TcR in fetal thymus. In contrast, the number of TcR gamma delta+ cells was reduced. We suggest that altered T cell development in transgenic mice directly or indirectly inhibits the accumulation of abnormal T cells in gld mice.
Animals↗
CD4-CD8+ T-cell receptor-alpha beta+ major histocompatibility complex class-II-specific T-cell clones isolated from aged athymic mice.
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Aging↗
Modulation of T cell responses with MHC-derived peptides.
T cells are activated by an interaction of their TCRs with a complex made up of antigenic peptide bound to the interhelical groove of MHC molecules. The helices lining the antigen binding groove of MHC molecules are felt to contribute several contact residues for TCR binding. Peptides derived from the amino acid sequences of these helices may be capable of modulating immune responses and aiding in the dissection of immune recognition. These studies address the effects of a peptide derived from the sequence of amino acids 68-83 of the IAk beta 1 domain (IAk 68-83) predicted to represent a portion of an antigen-binding helix on the IAk molecule. The IAk 68-83 peptide is bound by a monoclonal anti-IAk antibody and inhibits its binding to IAk-bearing cells. The IAk 68-83 peptide inhibits antigen-dependent activation of the IAk+con-albumin restricted T cell clone D10.G4, and this effect is more pronounced at lower doses of antigen-presenting cells. The free peptide has a small effect in limiting binding of anticlonotypic antibodies to D10.G4, and a multivalent form bound to BSA has a more pronounced effect in this regard. The BSA-peptide conjugate, when fluoresceinated, specifically stained D10.G4 cells, and this was specifically competed by unfluoresceinated IAk 68-83 peptide-BSA conjugate, as well as by anticlonotype. These results suggest that peptides derived from the predicted helical region of MHC class II molecules may have a direct interaction with T cell receptors. Such peptides may be capable of modulating immune responses in a physiologically significant manner.
Amino Acid Sequence↗
Response of V beta 8.1+ T cell clones to self Mls-1a: implications for the origin of autoreactive T cells.
Clonal deletion and anergy are two major mechanisms of self-tolerance. However, the molecular mechanisms underlying clonal deletion and anergy, as well as the threshold of TCR affinity/avidity required for these processes, are not known. Expression of the V beta 8.1 TCR correlates with the reactivity of the T cells to the minor lymphocyte stimulating locus-1a (Mls-1a) and T cells expressing this TCR are deleted in the thymus of Mls-1a mice. Similarly, in TCR V beta 8.1 transgenic mice, the number of CD4+CD8-T cells is reduced in Mls-1a mice. However, small numbers of CD4+CD8-T cells remain in the periphery of adult Mls-1a transgenic mice. We have generated T cell clones from TCR V beta 8.1 transgenic mice by stimulation of lymph node T cells with C57BL/6 alloantigens. Interestingly, CD4+CD8-V beta 8.1+ clones isolated from the transgenic mice of Mls-1a background responded to the self-antigen Mls-1a, to which they did not respond in primary assay. Reactive patterns of the clones were compared with clones derived from Mls-1b mice. Proliferation and cytokine production of the clones from Mls-1a mice to the self-antigen Mls-1a were generally reduced when compared with clones from Mls-1b mice. More importantly, T cell clones from Mls-1a mice required more Mls-1a antigen for their activation, and were more susceptible to the inhibitory effects of anti-CD4 antibody on the proliferative responses to Mls-1a than those from Mls-1b mice. These results suggest that the T cell receptor on clones derived from Mls-1a mice have functional but reduced affinity/avidity for self-antigen Mls-1a.
Animals↗
[Cholinergic modulation on stereotyped behavior and behavioral hypersensitivity (reverse tolerance) in rats].
The failure in the mutual balance between striatal/mesolimbic dopaminergic neurons and the inhibitory system, and a decreased activity of mesocortical dopaminergic neurons may account for biological base of paranoid schizophrenia. We tested this hypothesis by investigating stereotyped behavior and "reverse tolerance" in dopaminergic supersensitivity co-existing with a low-level activity of the inhibitory cholinergic system induced by the chronic administration of methamphetamine (MAP) 4 mg/kg in combination with scopolamine (SCOP) 0.5 mg/kg, in male Wistar rats. For investigating the influence of mesocortical dopaminergic neurons, experiments were designed to compare these behavioral responses in isolated rats, in which the activity of mesocortical dopaminergic neurons seemed to be reduced, to those in group-housed rats. The treatment with MAP plus SCOP produced significantly more potent effect in enhancing stereotyped behavior and "reverse tolerance" than the treatment with MAP only. Stereotyped behavior and "reverse tolerance" induced by the MAP plus SCOP treatment were more intense in isolated rats than in grouped rats. Effects of haloperidol (1 mg/kg) and pimozide (2 mg/kg or 5 mg/kg) on stereotyped behavior were less in MAP plus SCOP treated rats and isolated rats. The data may support a working hypothesis.
Animals↗
Origin and selection of peripheral CD4-CD8- T cells bearing alpha/beta T cell antigen receptors in autoimmune gld mice.
We have analyzed the origin and development of unusual CD4-CD8- alpha/beta T cell receptor-positive peripheral T cells produced in large numbers by mice homozygous for the gld mutation (C3H-gld/gld). These mice may be an important model for investigating processes controlling T cell development. Bone marrow transfers demonstrated that the gld defect was intrinsic to bone marrow-derived cells. Clonal deletion of potentially autoreactive cells was observed in peripheral gld CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells, as well as mature thymocytes. This suggests that gld CD4-CD8- T cells have passed through the thymus in ontogeny and that gld autoimmunity does not result from a general defect in elimination of self-reactive thymocytes. These observations, combined with demethylation of the CD8 gene in the CD4-CD8- population, support prior expression of CD4 and/or CD8 in gld CD4-CD8- T cell ontogeny, perhaps at a CD4+CD8+ stage. Steroid sensitivity of gld thymocytes and CD4-CD8- T cells was normal. Therefore, we found no gross abnormalities in two major mechanisms of inducible cell death in the gld thymus, the clonal deletion process associated with tolerance and the steroid-inducible endogenous endonuclease thought to be involved in apoptosis of unselected thymocytes. The data suggest that if gld CD4-CD8- T cells arise via escape from normal elimination in the thymus, they must do so by a novel defect in thymic selection (perhaps related to aberrant positive signals) and/or are expanded by an extrathymic process which allows clonal deletion to occur.
Animals↗
Inhibition of T cell development in thymic organ culture: implications for the mechanism of action of cyclosporin A.
We have examined the effects of the immunosuppressive drug cyclosporin A (CsA) on the phenotypic maturation of T cells in thymic organ cultures begun at day 16 of gestation. CsA specifically inhibited the generation of cells expressing high levels of alpha/beta TcR/CD3 complexes and a mature phenotype defined by CD4 and CD8 surface markers. Adding interleukin (IL) 1 beta, IL 2 or IL 4 failed to reverse the effects of CsA, and major histocompatibility complex class II expression in the thymic medulla was preserved. Possible mechanisms of CsA-mediated inhibition of T cell development are discussed.
Animals↗
T-cell receptor and autoimmune disease.
Since the genes encoding the TCR have been cloned, their structure, organization, pattern of rearrangement, diversification and expression in ontogeny have been classified. However, there are still many important questions to be addressed, such as the nature of thymic education, tolerance, the mechanism of MHC-restricted antigen recognition and the relation between TCR repertoire and autoimmunity. In the future, new approaches to study these issues, such as transgenic mice, X-ray crystallography, and severe combined immune deficiency mice reconstituted with human hematopoietic cells will lead to a more profound understanding of these questions. This will hopefully allow us to manipulate the immune response in different and more effective ways than are currently available.
Animals↗