35 results on '"Yuan, K."'
Search Results
2. Decreased FOXP3 levels in multiple sclerosis patients
- Author
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Halina Offner, Arthur A. Vandenbark, Nicole Culbertson, Yuan K. Chou, Leslie Spencer, Jianya Huan, Dennis Bourdette, Steven F. Ziegler, Richard M. Bartholomew, and Gregory G. Burrows
- Subjects
Adult ,Genetic Markers ,Male ,Multiple Sclerosis ,medicine.drug_class ,chemical and pharmacologic phenomena ,Biology ,Immune tolerance ,Cellular and Molecular Neuroscience ,Reference Values ,T-Lymphocyte Subsets ,medicine ,Humans ,RNA, Messenger ,IL-2 receptor ,Receptor ,Multiple sclerosis ,T-cell receptor ,FOXP3 ,Forkhead Transcription Factors ,Receptors, Interleukin-2 ,hemic and immune systems ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Estrogen ,CD4 Antigens ,Immunology ,Female ,Ligation - Abstract
Autoimmune diseases such as multiple sclerosis (MS) may result from the failure of tolerance mechanisms to prevent expansion of pathogenic T cells. Our study is the first to establish that MS patients have abnormalities in FOXP3 message and protein expression levels in peripheral CD4+CD25+ T cells (Tregs) that are quantitatively related to a reduction in functional suppression induced during suboptimal T-cell receptor (TCR) ligation. Of importance, this observation links a defect in functional peripheral immunoregulation to an established genetic marker that has been unequivocally shown to be involved in maintaining immune tolerance and preventing autoimmune diseases. Diminished FOXP3 levels thus indicate impaired immunoregulation by Tregs that may contribute to MS. Future studies will evaluate the effects of therapies known to influence Treg cell function and FOXP3 expression, including TCR peptide vaccination and supplemental estrogen. © 2005 Wiley-Liss, Inc.
- Published
- 2005
3. HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes
- Author
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Chella S. David, Cathleen Rich, Thomas P. Finn, Rony Dahan, Arthur A. Vandenbark, Jason Link, Halina Offner, Richard E. Jones, and Yuan K. Chou
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Male ,musculoskeletal diseases ,Multiple Sclerosis ,Proteolipid protein 1 ,Molecular Sequence Data ,Antigen presentation ,Mice, Transgenic ,Human leukocyte antigen ,Lymphocyte Activation ,Epitope ,Cell Line ,Myelin oligodendrocyte glycoprotein ,Mice ,Cellular and Molecular Neuroscience ,Myelin ,Risk Factors ,immune system diseases ,medicine ,Animals ,Humans ,Amino Acid Sequence ,skin and connective tissue diseases ,Cells, Cultured ,Mice, Knockout ,Antigen Presentation ,biology ,Immunodominant Epitopes ,Multiple sclerosis ,Immunogenicity ,Myelin Basic Protein ,HLA-DR Antigens ,medicine.disease ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,Immunology ,biology.protein ,Female ,Myelin-Oligodendrocyte Glycoprotein ,Myelin Proteins ,HLA-DRB1 Chains - Abstract
Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501-restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.
- Published
- 2004
4. Recombinant TCR Ligand Induces Early TCR Signaling and a Unique Pattern of Downstream Activation
- Author
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Roberto Meza-Romero, Jeffery L. Mooney, Halina Offner, Yuan K. Chou, Arthur A. Vandenbark, Chunhe Wang, Gregory G. Burrows, and Jianya Huan
- Subjects
CD3 Complex ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,T cell ,Guinea Pigs ,Molecular Sequence Data ,Immunology ,Receptors, Antigen, T-Cell ,Ligands ,Lymphocyte Activation ,Mice ,Histocompatibility Antigens ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Immunology and Allergy ,Amino Acid Sequence ,Calcium Signaling ,HLA-DR2 Antigen ,Phosphorylation ,Transcription factor ,MHC class II ,Hybridomas ,ZAP-70 Protein-Tyrosine Kinase ,NFATC Transcription Factors ,biology ,Kinase ,T-cell receptor ,NF-kappa B ,Nuclear Proteins ,Myelin Basic Protein ,NFAT ,Protein-Tyrosine Kinases ,Molecular biology ,Peptide Fragments ,Recombinant Proteins ,Rats ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Rats, Inbred Lew ,biology.protein ,Interleukin-2 ,Mitogen-Activated Protein Kinases ,Signal transduction ,Transcription Factors - Abstract
Recombinant TCR ligands (RTLs) consisting of covalently linked α1 and β1 domains of MHC class II molecules tethered to specific antigenic peptides represent minimal TCR ligands. In a previous study we reported that the rat RTL201 construct, containing RT1.B MHC class II domains covalently coupled to the encephalitogenic guinea pig myelin basic protein (Gp-MBP72–89) peptide, could prevent and treat actively and passively induced experimental autoimmune encephalomyelitis in vivo by selectively inhibiting Gp-MBP72–89 peptide-specific CD4+ T cells. To evaluate the inhibitory signaling pathway, we tested the effects of immobilized RTL201 on T cell activation of the Gp-MBP72–89-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP72–89 peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3ζ p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3ε treatment produced stronger activation of these cellular events with additional activation of NF-κB and extracellular signal-regulated kinases as well as long term increased IL-2 production. These results demonstrate that RTLs can bind directly to the TCR and modify T cell behavior through a partial activation mechanism, triggering specific downstream signaling events that deplete intracellular calcium stores without fully activating T cells. The resulting Ag-specific activation of the transcription factor NFAT uncoupled from the activation of NF-κB or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4+ T cells.
- Published
- 2003
5. Rudimentary TCR Signaling Triggers Default IL-10 Secretion by Human Th1 Cells
- Author
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Arthur A. Vandenbark, Tohru Yoshioka, Yuan K. Chou, Joseph Kim, Masayuki Ikeda, Halina Offner, Gregory G. Burrows, Dennis Bourdette, Justin W. Chang, Nicole Culbertson, Chunhe Wang, Charles N. Allen, Deborah A. Lewinsohn, David M. Lewinsohn, and Thomas P. Finn
- Subjects
Multiple Sclerosis ,T cell ,Immunology ,Cell ,Fusion Proteins, bcr-abl ,Receptors, Antigen, T-Cell ,Biology ,Ligands ,medicine ,Humans ,Immunology and Allergy ,Secretion ,Calcium Signaling ,HLA-DR2 Antigen ,Kinase activity ,T-cell receptor ,Myelin Basic Protein ,Th1 Cells ,Peptide Fragments ,Clone Cells ,Interleukin-10 ,Myelin basic protein ,Cell biology ,Interleukin 10 ,medicine.anatomical_structure ,Biochemistry ,Genes, T-Cell Receptor beta ,biology.protein ,Phosphorylation ,Signal Transduction - Abstract
Understanding the process of inducing T cell activation has been hampered by the complex interactions between APC and inflammatory Th1 cells. To dissociate Ag-specific signaling through the TCR from costimulatory signaling, rTCR ligands (RTL) containing the α1 and β1 domains of HLA-DR2b (DRA*0101:DRB1*1501) covalently linked with either the myelin basic protein peptide 85–99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provide a minimal ligand for peptide-specific TCRs. When incubated with peptide-specific Th1 cell clones in the absence of APC or costimulatory molecules, only the cognate RTL induced partial activation through the TCR. This partial activation included rapid TCR ζ-chain phosphorylation, calcium mobilization, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic changes. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had reduced proliferation and secreted less IFN-γ; IL-10 production persisted. These findings reveal for the first time the rudimentary signaling pattern delivered by initial engagement of the external TCR interface, which is further supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases.
- Published
- 2001
6. Diminished frequency of interleukin-10-secreting, T-cell receptor peptide-reactive T cells in multiple sclerosis patients might allow expansion of activated memory T cells bearing the cognate BV gene
- Author
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Yuan K. Chou, Arthur A. Vandenbark, David Barnes, Halina Offner, Michele Mass, Nicole Culbertson, Tom Finn, Kevin Hicks, Dennis Bourdette, Antony C. Bakke, and Ruth H. Whitham
- Subjects
Adult ,Male ,Multiple Sclerosis ,Receptors, Antigen, T-Cell, alpha-beta ,Molecular Sequence Data ,Enzyme-Linked Immunosorbent Assay ,Biology ,Lymphocyte Activation ,Interferon-gamma ,Cellular and Molecular Neuroscience ,Interleukin 21 ,T-Lymphocyte Subsets ,Concanavalin A ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,IL-2 receptor ,Aged ,Interleukin 3 ,ZAP70 ,Vaccination ,Middle Aged ,Th1 Cells ,Natural killer T cell ,Peptide Fragments ,Interleukin-10 ,Interleukin 10 ,Gene Expression Regulation ,Immunology ,Interleukin 12 ,Female ,Immunologic Memory - Abstract
T cells responsive to T-cell receptor (TCR) determinants may regulate pathogenic Th1 responses in patients with multiple sclerosis (MS) through interleukin (IL)-10-dependent bystander suppression. In this study, innate IL-10- and interferon (IFN)-γ-secreting T cells responsive to TCR peptides were quantified in peripheral blood mononuclear cells of MS patients and healthy controls (HC) using the ELISPOT assay. Most HC had vigorous IL-10 but low IFN-γ frequencies to BV5S2 and BV6S1 peptides. In contrast, MS patients had significantly lower IL-10 frequency responses to the TCR peptides but normal responses to concanavalin A. Patients undergoing TCR-peptide vaccination had moderate responses that fluctuated in concert with vaccination. In an MS patient and HC, expression of BV6S1 by activated memory T cells was inversely associated with the presence of IL-10-secreting BV6S1-reactive T cells. These results suggest that MS patients have diminished frequencies of innate TCR-reactive T cells that may allow oligoclonal expansion of activated autoreactive Th1 effector cells expressing cognate V genes. J. Neurosci. Res. 66:171–176, 2001. Published 2001 Wiley-Liss, Inc.
- Published
- 2001
7. Differential susceptibility of human Th1 versus T h 2 cells to induction of anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells
- Author
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David Barnes, Dennis Bourdette, Arthur A. Vandenbark, Ruth H. Whitham, Tom Finn, Halina Offner, Steven D. Miller, Johnan Kaleeba, Ian Robey, Yuan K. Chou, and Bruce F. Bebo
- Subjects
Multiple Sclerosis ,Immunology ,Antigen presentation ,Receptors, Antigen, T-Cell ,Antigen-Presenting Cells ,Apoptosis ,Biology ,Th2 Cells ,CD28 Antigens ,Antigen ,Ethyldimethylaminopropyl Carbodiimide ,Tetanus Toxoid ,Humans ,Simplexvirus ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,Clonal Anergy ,Antigen Presentation ,CD40 ,T-cell receptor ,CD28 ,Myelin Basic Protein ,General Medicine ,Th1 Cells ,Molecular biology ,Interleukin-10 ,Cell biology ,Cross-Linking Reagents ,biology.protein ,Interleukin-2 ,Interleukin-5 ,Signal Transduction - Abstract
Antigen-coupled antigen-presenting cells (APC) serve as potent tolerogens for inhibiting immune responses in vivo and in vitro, apparently by providing an antigen-specific signal through the TCR in the absence of co-stimulation. Although this approach has been well studied in rodents, little is known about its effects on human T cells. We evaluated the specificity and mechanisms of tolerization of human T cells in vitro using monocyte-enriched adherent cells that were pulsed with antigen and treated with the cross-linker, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI). Autologous antigen-coupled APC selectively tolerized T cells of the T(h)1 but not T(h)2 lineage through a mechanism that involved both antigen-specific and antigen-non-specific elements. The tolerization process was dependent on the ECDI and antigen concentration, and the coupling time, and was reflected by initial up-regulation of CD25. However, upon re-stimulation with fresh APC and antigen, tolerized T(h)1 cells failed to proliferate or to produce T(h)1 cytokine message or secreted protein, had decreased expression of CD25, CD28 and B7 and increased expression of MHC class II molecules, and demonstrated an enhanced commitment to apoptosis. T(h)1 cell tolerization could be prevented by adding anti-CD28 antibody, IL-2 or untreated APC at the same time as the ECDI/antigen-coupled APC, or reversed by adding anti-CD28 antibody or IL-2 upon re-stimulation with fresh APC plus antigen. Thus, the tolerizing effect of ECDI/antigen-coupled APC on human T(h)1 cells appears to involve a reversible anergy mechanism leading to apoptosis, whereby the targeted T cells receive full or partial activation through the TCR, without coordinate co-stimulation. These data suggest dichotomous signaling requirements for inactivating cells of the T(h)1 and T(h)2 lineages that may have important implications for treatment of T(h)1-mediated autoimmune or inflammatory diseases.
- Published
- 2000
8. Immunity to T Cell Receptor Peptides in Multiple Sclerosis. III. Preferential Immunogenicity of Complementarity-Determining Region 2 Peptides from Disease-Associated T Cell Receptor BV Genes*
- Author
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Dennis N. Bourdette, Yuan K. Chou, Ruth H. Whitham, Jane Buckner, Hi Jong Kwon, Gerald T. Nepom, Abigail Buenafe, Shelley A. Cooper, Mark Allegretta, George A. Hashim, Halina Offner, and Arthur A. Vandenbark
- Subjects
Immunology ,Immunology and Allergy - Abstract
Vaccination with synthetic TCR peptides from the BV5S2 complementarity-determining region 2 (CDR2) can boost significantly the frequency of circulating CD4+ peptide-specific Th2 cells in multiple sclerosis (MS) patients, with an associated decrease in the frequency of myelin basic protein (MBP)-reactive Th1 cells and possible clinical benefit. To evaluate the immunogenicity of CDR2 vs other regions of the TCR, we vaccinated seven MS patients with overlapping BV5S2 peptides spanning amino acids 1–94. Six patients responded to at least one of three overlapping or substituted CDR2 peptides possessing a core epitope of residues 44–52, and one patient also responded to a CDR1 peptide. Of the CDR2 peptides, the substituted (Y49T)BV5S2-38–58 peptide was the most immunogenic but cross-reacted with the native sequence and had the strongest binding affinity for MS-associated HLA-DR2 alleles, suggesting that position 49 is an MHC rather than a TCR contact residue. Two MS patients who did not respond to BV5S2 peptides were immunized successfully with CDR2 peptides from different BV gene families overexpressed by their MBP-specific T cells. Taken together, these results suggest that a widely active vaccine for MS might well involve a limited set of slightly modified CDR2 peptides from BV genes involved in T cell recognition of MBP.
- Published
- 1998
9. Superantigens induce IL-17 production from polarized Th1 clones
- Author
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Cong Qiu Chu, Yuan K. Chou, and Kentaro Yomogida
- Subjects
Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,Stimulation ,Biochemistry ,Article ,Myelin oligodendrocyte glycoprotein ,Interferon-gamma ,Cell polarity ,medicine ,Superantigen ,Immunology and Allergy ,Humans ,Interferon gamma ,Molecular Biology ,Superantigens ,biology ,Interleukin-17 ,Histocompatibility Antigens Class II ,Cell Polarity ,Hematology ,Th1 Cells ,In vitro ,Inflammatory mediator ,biology.protein ,Interleukin 17 ,Inflammation Mediators ,medicine.drug - Abstract
Differentiation of naïve CD4(+) T cells has been considered to be an irreversible event and, in particular, the plasticity is believed to be completely lost in Th1 subset in vitro after multiple stimulations. However, here we demonstrate that highly polarized myelin oligodendrocyte glycoprotein (MOG)- and herpes simples virus-specific Th1 clones were still capable of producing IL-17 upon superantigen stimulation. Anti-MHC class-II and anti-TCR αβ chains partially blocked superantigen-induced IL-17 production. These findings suggest that fully differentiated Th1 cells still have capability to produce cytokines of other Th subsets and production of IL-17 by MOG-specific Th1 cells may have implication in initiation and/or exacerbation of neurological autoimmune diseases.
- Published
- 2012
10. A novel regulatory pathway for autoimmune disease: Binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance
- Author
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Roberto Meza-Romero, Rony Dahan, Jianya Huan, Halina Offner, Yuan K. Chou, Abigail C. Buenafe, Gregory G. Burrows, Gil Benedek, Jeffery L. Mooney, Arthur A. Vandenbark, Yoram Reiter, and Shayne Andrew
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,CD74 ,T cell ,Recombinant Fusion Proteins ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Article ,Monocytes ,Immune tolerance ,Autoimmune Diseases ,Mice ,Antigen ,MHC class I ,medicine ,Immune Tolerance ,Immunology and Allergy ,Animals ,Macrophage Migration-Inhibitory Factors ,MHC class II ,CD11b Antigen ,biology ,Experimental autoimmune encephalomyelitis ,Histocompatibility Antigens Class II ,Membrane Proteins ,medicine.disease ,Molecular biology ,Cell biology ,Antigens, Differentiation, B-Lymphocyte ,Intramolecular Oxidoreductases ,medicine.anatomical_structure ,biology.protein ,Macrophage migration inhibitory factor - Abstract
Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands - RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b(+) mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.
- Published
- 2012
11. T cell receptor V? gene usage in the recognition of myelin basic protein by cerebrospinal fluid- and blood-derived T cells from patients with multiple sclerosis
- Author
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William J. Morrison, J. Atherton, Dennis Bourdette, J. Lane, Ruth H. Whitham, R. Dedrick, G.A. Hashim, Halina Offner, Arthur A. Vandenbark, E. Spoor, A. C. Burenafe, and Yuan K. Chou
- Subjects
Adult ,Male ,Multiple Sclerosis ,Receptors, Antigen, T-Cell, alpha-beta ,Molecular Sequence Data ,Biology ,Polymerase Chain Reaction ,Cellular and Molecular Neuroscience ,Myelin ,Cerebrospinal fluid ,Recurrence ,medicine ,Humans ,Receptor ,Aged ,Base Sequence ,Multiple sclerosis ,T-cell receptor ,Myelin Basic Protein ,T lymphocyte ,Middle Aged ,medicine.disease ,Myelin basic protein ,Phenotype ,medicine.anatomical_structure ,Gene Expression Regulation ,Chronic Disease ,Immunology ,biology.protein ,Female ,Antibody ,Cell Division - Abstract
Because of its proximity to the central nervous system, the cerebrospinal fluid (CSF) represents an important source of T cells that potentially could mediate putative autoimmune diseases such as multiple sclerosis (MS). To overcome the low CSF cellularity, we evaluated culture conditions that could expand CSF T cells, with a focus on the expression of T-cell receptor V beta genes utilized by T cells specific for the potentially encephalitogenic autoantigen myelin basic protein (BP). Expansion of "activated" CSF cells with IL-2/IL-4 plus accessory cells optimally retained BP-responsive T cells that over-expressed V beta 1, V beta 2, V beta 5, or V beta 18, compared to expansion using supernatants from PHA-stimulated blood cells, or anti-CD3 antibody that led to different V gene bias and rare reactivity to BP. Sequential evaluation of paired CSF and blood samples from a relapsing remitting MS patient indicated that BP-reactive T cells were present in CSF during the period of clinical activity, and the pattern of BP recognition in CSF was partially reflected in blood, even after CSF reactivity had dissipated during remission. Over-expressed V beta genes were not always constant, however, since in three sequential evaluations of a chronic progressive MS patient, V beta genes over-expressed in the first BP-reactive CSF switched to a different V beta gene bias that was present in the second and third CSF samples. Blood samples reflected each pattern of CSF V beta gene bias, but retained the initial bias for at least 4 months after its disappearance from CSF. These data indicate that selective expansion of IL-2/IL-4-responsive CSF cells favors growth of the BP-reactive subpopulation, and, in a limited number of patients studied, reflected clinical disease activity. In comparison, blood T cells provided a partial but longer lasting reflection of the CSF BP reactivity and V beta gene bias.
- Published
- 1994
12. Human myelin basic protein (MBP) epitopes recognized by mouse MBP-selected T cell lines from multiple sclerosis patients
- Author
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Jeanette Atherton, Yuan K. Chou, Dennis Bourdette, Ruth Whithman, Richard E. Jones, George A. Hashim, Halina Offner, and Arthur A. Vandenbark
- Subjects
Multiple Sclerosis ,T-Lymphocytes ,T cell ,Molecular Sequence Data ,Immunology ,Mice, SCID ,Cross Reactions ,Biology ,Epitope ,Cell Line ,Epitopes ,Mice ,Chimera (genetics) ,medicine ,Animals ,Humans ,Immunology and Allergy ,Amino Acid Sequence ,Severe combined immunodeficiency ,MHC class II ,Histocompatibility Antigens Class I ,Experimental autoimmune encephalomyelitis ,Histocompatibility Antigens Class II ,Myelin Basic Protein ,MHC restriction ,medicine.disease ,Peptide Fragments ,Myelin basic protein ,medicine.anatomical_structure ,Neurology ,biology.protein ,Neurology (clinical) - Abstract
We investigated whether myelin basic protein (MBP)-reactive T cells from multiple sclerosis (MS) patients can recognize mouse MBP since this is an expected requirement for the transfer of experimental autoimmune encephalomyelitis (EAE) into severe combined immunodeficiency (SCID) mouse-human chimeras. Peripheral blood mononuclear cells from 11 MS patients were analyzed for in vitro proliferation to mouse MBP. Six patients (55%) responded to mouse MBP at the first or second stimulation. Five T cell lines, selected with mouse MBP from five MS patients, were analyzed for their proliferation to mouse and human MBP and to a panel of synthetic peptides of human MBP. Four of the five lines recognized mouse MBP. In vitro proliferation was restricted by MHC class II in one line tested for MHC restriction. One of the five lines recognized whole human MBP and all five of the lines responded to at least one of the five synthetic peptides corresponding to human MBP residues 8-28, 67-90, 84-102, 87-99 or 130-149. These results show that MS patient T cells recognize mouse MBP and suggest that distinct human MBP epitopes are immunologically cross-reactive with epitopes of mouse MBP.
- Published
- 1994
13. Epitope specificity and V gene expression of cerebrospinal fluid T cells specific for intact versus cryptic epitopes of myelin basic protein
- Author
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Halina Offner, Ruth H. Whitham, Yuan K. Chou, George A. Hashim, Arthur A. Vandenbark, Dennis Bourdette, and Karuturi Satyanarayana
- Subjects
Adult ,Male ,Multiple Sclerosis ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Antigen presentation ,Gene Expression ,Epitope ,Epitopes ,Immune system ,Gene expression ,medicine ,Humans ,Immunology and Allergy ,Gene ,Cerebrospinal Fluid ,biology ,Multiple sclerosis ,T-cell receptor ,Myelin Basic Protein ,Middle Aged ,medicine.disease ,Myelin basic protein ,Neurology ,biology.protein ,Female ,Neurology (clinical) ,Nervous System Diseases - Abstract
Recent evidence supports the possible involvement of myelin basic protein (BP) as one of the target autoantigens in multiple sclerosis (MS), including elevated frequencies of MS blood and cerebrospinal fluid (CSF) T cells, and the presence in MS plaque tissue of V beta gene sequences and CDR3 motifs characteristic of BP-reactive T cells. Because of its proximity to the target organ, the CSF has long been thought to harbor T cells involved in the pathogenic process. In order to evaluate their frequency and response characteristics, BP-reactive T cells were isolated by limiting dilution from the CSF of patients with MS and other neurological diseases (OND) for quantitation and determination of epitope specificity and V alpha and V beta gene expression. In addition to isolates responsive to intact BP epitopes that were present at a significantly higher frequency in MS versus OND CSF, we here describe a second clonotype responsive to 'cryptic' BP epitopes that is present at approximately equal frequencies in MS and OND patients. In spite of their difference in recognition of intact versus 'cryptic' BP determinants, both clonotypes predominantly recognized epitopes in the N terminal half of human BP, using a similar V gene repertoire that included biased use of V alpha 2 and to a lesser degree V beta 7 and V beta 18. These V gene biases were not related to the epitope specificity of the T cells, indicating that V gene selection is not epitope-driven. These data suggest that there is differential recognition of intact versus 'cryptic' BP determinants in MS versus OND patients that may be related to the processing and presentation of BP to the immune system.
- Published
- 1993
14. Human Cd8+ T Cell Clone Regulates Autologous Cd4+ Myelin Basic Protein Specific T Cells
- Author
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Paula Henderikx, Halina Offner, Richard E. Jones, Arthur A. Vandenbark, Yuan K. Chou, Brian L. Kotzin, and George A. Hashim
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Receptors, Antigen, T-Cell, alpha-beta ,T cell ,Immunology ,Clone (cell biology) ,Autoimmunity ,Lymphocyte Activation ,Major histocompatibility complex ,Polymerase Chain Reaction ,HLA Antigens ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,biology ,Histocompatibility Antigens Class I ,T-cell receptor ,Histocompatibility Antigens Class II ,Antibodies, Monoclonal ,Myelin Basic Protein ,T lymphocyte ,Virology ,Molecular biology ,Clone Cells ,Myelin basic protein ,medicine.anatomical_structure ,biology.protein ,CD8 - Abstract
Normal human CD8+ T cell clones were co-isolated from the same culture wells as CD4+ T effector cell clones specific for myelin basic protein (MBP). Microcultures from which the CD8+ clones were isolated initially proliferated weakly to whole MBP and to an MBP peptide spanning residues 90-170. This pattern of response was similar to strongly proliferating wells that yielded CD4+ T cell clones specific for the 90-170 peptide. After repeated stimulation, however, no response to MBP or MBP 90-170 was detected, even though the number of cells increased after stimulation. Phenotyping and TCR analyses revealed the presence of two CD8+, CD4-, IL-2R+ T cell isolates that expressed a single V beta gene (V beta 17) that differed from the CD4+ isolates that uniformly expressed V beta 14. One of these CD8+ clones (C9) inhibited the antigen-driven proliferation of an autologous MBP 90-170 reactive clone but not an autologous clone specific for Herpes simplex virus (HSV), without affecting MHC non-restricted mitogen responses of the same clones. Moreover, C9 did not inhibit heterologous CD4+ T cell clones specific for MBP 1-38 or 90-170. A culture supernatant of the CD8+ clone showed the same pattern but lower levels of inhibition. C9 had mild cytolytic activity when incubated at high ratios with an autologous MBP-specific CD4+ clone. Lysis was blocked completely by anti-MHC class I antibodies, but not by anti-MHC II antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
15. Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis
- Author
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Arthur A. Vandenbark, Marc Better, Halina Offner, Joseph M. Forrester, Joyce Lafferty, Yuan K. Chou, Brian L. Kotzin, Satyanarayana Karuturi, and Glenn Evan Nedwin
- Subjects
Multiple Sclerosis ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,T cell ,Molecular Sequence Data ,Immunogenetics ,Polymerase Chain Reaction ,Myelin ,medicine ,Humans ,T-Cell Receptor Beta Chain ,Beta (finance) ,Multidisciplinary ,Base Sequence ,biology ,Multiple sclerosis ,T-cell receptor ,Genetic Variation ,Myelin Basic Protein ,medicine.disease ,Clone Cells ,Myelin basic protein ,medicine.anatomical_structure ,Genes ,Oligodeoxyribonucleotides ,CD4 Antigens ,Immunology ,biology.protein ,Research Article - Abstract
Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cell receptor variable region genes was analyzed. A remarkable bias for use of beta-chain variable region (V beta) 5.2 and, to a lesser extent, V beta 6.1 was seen among BP-specific clones from patients but not from controls. The preferential use of V beta 5.2 for BP recognition did not reflect altered expression of this V beta in the peripheral repertoire. Interestingly, shared V beta 5.2 usage was apparent for clones specific for different BP determinants, even when derived from the same individual. The concurrent demonstration by others (J. R. Oksenberg, M. A. Panzara, A. B. Begovich, H. Erlich, R. Murray, M. Sherritt, S. Stuart, C. C. Bernard, and L. Steinman, personal communication) that T cells within demyelinating areas of multiple sclerosis brains preferentially express V beta 5.2 and V beta 6.1 suggests that the BP-specific clones derived from blood may be relevant to disease pathogenesis. These findings may have important implications for the treatment of multiple sclerosis.
- Published
- 1991
16. Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis
- Author
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Dennis Bourdette, Marci Agotsch, Arthur A. Vandenbark, Jianya Huan, Richard Bartholomew, Dorian LaTocha, Ruth H. Whitham, Halina Offner, Jesus Lovera, Vijayshree Yadav, Georgia Theofan, Michele Mass, Nicole Culbertson, June Milano, and Yuan K. Chou
- Subjects
Adult ,Male ,Multiple Sclerosis ,Immunology ,Receptors, Antigen, T-Cell ,Autoimmunity ,Nerve Tissue Proteins ,Biology ,Peripheral blood mononuclear cell ,Autoantigens ,T-Lymphocytes, Regulatory ,Antigen ,Immune Tolerance ,Immunology and Allergy ,Humans ,IL-2 receptor ,Aged ,T-cell receptor ,Vaccination ,Interleukin ,FOXP3 ,Forkhead Transcription Factors ,Original Articles ,Middle Aged ,Virology ,Complementarity Determining Regions ,Genes, T-Cell Receptor ,Vaccines, Subunit ,Peptide vaccine ,Female ,Immunologic Memory - Abstract
Therapeutic vaccination using T-cell receptor (TCR) peptides from V genes commonly expressed by potentially pathogenic T cells remains an approach of interest for treatment of multiple sclerosis (MS) and other autoimmune diseases. We developed a trivalent TCR vaccine containing complementarity determining region (CDR) 2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T cells. To evaluate induction of regulatory T-cell subtypes, immunological and clinical parameters were followed in 23 treatment-naive subjects with relapsing-remitting or progressive MS who received 12 monthly injections of the trivalent peptide vaccine over 1 year in an open-label study design. Prior to vaccination, subjects had reduced expression of forkhead box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive cells compared with healthy control donors. After three or four injections, most vaccinated MS subjects developed high frequencies of circulating interleukin (IL)-10-secreting T cells specific for the injected TCR peptides and significantly enhanced expression of FoxP3 by regulatory T cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- peripheral blood mononuclear cells (PBMC). At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels, exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed neuroantigen but not recall antigen responses. These findings demonstrate that therapeutic vaccination using only three commonly expressed BV gene determinants can induce an expanded immunoregulatory network in vivo that may optimally control complex autoreactive responses that characterize the inflammatory phase of MS.
- Published
- 2007
17. Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells
- Author
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Brian L. Scott, Jianya Huan, Gregory G. Burrows, Yuan K. Chou, Timothy S. Keizer, Roberto Meza-Romero, Arthur A. Vandenbark, Douglas G. Mack, Andrew P. Fontenot, David M. Edwards, and Mark T. Mccleskey
- Subjects
CD4-Positive T-Lymphocytes ,HLA-DP Antigens ,T cell ,Immunology ,Molecular Sequence Data ,Receptors, Antigen, T-Cell ,chemistry.chemical_element ,Peptide binding ,Human leukocyte antigen ,Ligands ,Cell Line ,Berylliosis ,Mice ,Antigen ,medicine ,Immunology and Allergy ,Animals ,Humans ,Amino Acid Sequence ,HLA-DP beta-Chains ,MHC class II ,biology ,Molecular biology ,Recombinant Proteins ,respiratory tract diseases ,Rats ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Cell culture ,Chronic Disease ,biology.protein ,Beryllium ,Beryllium Disease - Abstract
Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the α-1 and β-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4-pulsed, plate-bound rHLA-DP2 molecules induced IFN-γ secretion. In addition, pretreatment of beryllium-specific CD4+ T cells with BeSO4-pulsed, plate-bound HLA-DP2 blocked proliferation and IL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.
- Published
- 2006
18. Self-presentation of beryllium by BAL CD4+ T cells: T cell-T cell interactions and their potential role in chronic beryllium disease
- Author
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Gregory G. Burrows, Andrew P. Fontenot, Douglas G. Mack, David M. Edwards, Dorian LaTocha, Yuan K. Chou, and Arthur A. Vandenbark
- Subjects
CD4-Positive T-Lymphocytes ,Lymphocyte ,T cell ,Immunology ,Antigen presentation ,Cell Communication ,Lymphocyte Activation ,Berylliosis ,Interferon-gamma ,Antigen ,medicine ,Immunology and Allergy ,Humans ,CD134 ,MHC class II ,Antigen Presentation ,biology ,Tumor Necrosis Factor-alpha ,Histocompatibility Antigens Class II ,CD28 ,Molecular biology ,respiratory tract diseases ,medicine.anatomical_structure ,biology.protein ,Interleukin-2 ,Beryllium ,Bronchoalveolar Lavage Fluid ,CD80 - Abstract
Chronic beryllium disease (CBD) is characterized pathologically by granulomatous inflammation in the lung, composed of a large core of epithelioid cells surrounded by a dense shell of CD4+ T cells. Using beryllium-specific CD4+ T cell lines derived from the bronchoalveolar lavage (BAL) fluid of CBD patients, we show that purified CD4+ T cells produced significant amounts of IFN-gamma and TNF-alpha upon exposure to beryllium in the absence of antigen-presenting cells (APC). However, unlike BAL T cells stimulated by beryllium in the presence of APC, self-presentation by BAL T cells did not induce detectable IL-2 production, and in its absence these activated T cells die from programmed cell death. Resting BAL CD4+ T cells constitutively express high levels of HLA-DP, lymphocyte function-associated antigen 1 (LFA-1) and ICAM-3. When stimulated with beryllium/APC, the adhesion molecule ICAM-1 was up-regulated, as well as several costimulation molecules including CD28, OX-40 (CD134), 4-1-BB (CD137) and B7-1 (CD80). Notably, CD28 was not up-regulated during self-presentation by BAL T cells, and these cells do not express OX-40L, suggesting that lack of appropriate costimulation was responsible for programmed cell death observed upon beryllium self-presentation. Restricting anti-MHC class II mAb completely eliminated beryllium-induced T cell proliferation during self-presentation and significantly reduced IFN-gamma and TNF-alpha production. Our data demonstrate for the first time that self-presentation by BAL T cells in response to beryllium can occur ex vivo, in the absence of professional APC, with a specific dependence on T cell-expressed MHC class II molecules and exogenous IL-2 for survival.
- Published
- 2006
19. AlphaB-crystallin-reactive T cells from knockout mice are not encephalitogenic
- Author
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Chunhe Wang, Halina Offner, Johannes M. van Noort, Jason M. Link, Yuan K. Chou, Michael Afentoulis, Arthur A. Vandenbark, Cathleen Rich, and Eric F. Wawrousek
- Subjects
Proteolipid protein 1 ,Encephalomyelitis, Autoimmune, Experimental ,T cell ,T-Lymphocytes ,Immunology ,Molecular Sequence Data ,Lymphocyte Activation ,Immune tolerance ,Myelin oligodendrocyte glycoprotein ,Mice ,medicine ,Immunology and Allergy ,Animals ,Amino Acid Sequence ,Antigen-presenting cell ,Glycoproteins ,Mice, Knockout ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Experimental autoimmune encephalomyelitis ,Peripheral tolerance ,alpha-Crystallin B Chain ,medicine.disease ,Molecular biology ,Peptide Fragments ,Myelin basic protein ,medicine.anatomical_structure ,Neurology ,biology.protein ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,Lymph Nodes ,Spleen - Abstract
Alpha B-crystallin (αB) is a small heat shock protein that is strongly up-regulated in multiple sclerosis (MS) brain tissue, and can induce strong T cell responses. Assessing a potential encephalitogenic function for αB protein in MS and experimental autoimmune encephalomyelitis (EAE) has been challenging due to its ubiquitous expression that likely maintains central and peripheral tolerance to this protein in mice. To address this issue, we obtained αB-knockout (αB-KO) mice in H-2b background that lack immune tolerance to αB protein, and thus are capable of developing αB-specific T cells that could be tested for encephalitogenic activity after transfer into αB-expressing wild type (WT) mice. We found that T cell lines from spleens of αB protein-immunized αB-KO mice proliferated strongly to αB protein itself, and the majority of T cells were CD4+ and capable of secreting pro-inflammatory Th1 cytokines upon restimulation. However, transfer of such αB-reactive T cells back into WT recipients was not sufficient to induce EAE, compared to the transfer of mouse MOG-35-55 peptide-reactive T cells from the same donors that induced severe EAE in recipients. Moreover, αB-specific T cells failed to augment severity of actively induced EAE in WT mice that were expressing high levels of αB message in the CNS at the time of transfer. These results suggest that αB-specific T cells are immunocompetent but not encephalitogenic in 129SvEv mice, and that immune tolerance may not be the main factor that limits the encephalitogenic potential of αB. © 2006 Elsevier B.V. All rights reserved. Chemicals / CAS: crystallin, 11046-99-4; encephalitogenic protein, 29705-91-7; alpha-Crystallin B Chain; Glycoproteins; myelin oligodendrocyte glycoprotein (35-55); Peptide Fragments
- Published
- 2006
20. IL-7 enhances Ag-specific human T cell response by increasing expression of IL-2R alpha and gamma chains
- Author
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David Barnes, Abigail C. Buenafe, Halina Offner, Arthur A. Vandenbark, Yuan K. Chou, Susan Murray, Dennis Bourdette, Ruth H. Whitham, Mark Allegretta, Laura Unsicker, Ian Robey, and Thomas P. Finn
- Subjects
CD4-Positive T-Lymphocytes ,Cell Survival ,Immunology ,Antigens, CD19 ,Thymus Gland ,Biology ,CD8-Positive T-Lymphocytes ,Immunophenotyping ,Interleukin 21 ,Interferon-gamma ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,IL-2 receptor ,Antigen-presenting cell ,Interleukin 3 ,CD40 ,CD11 Antigens ,Interleukin-7 ,Receptors, Interleukin-2 ,Natural killer T cell ,Molecular biology ,CD56 Antigen ,Clone Cells ,Neurology ,Interleukin 12 ,biology.protein ,Interleukin-2 ,Neurology (clinical) ,Cell Division - Abstract
Interleukin-7 has demonstrated potent enhancing effects on the growth and differentiation of several immature cell types, including thymocytes, and on survival of resting and antigen activated T cells. In this study, we evaluated the effects of IL-7 on post-thymic antigen-specific T cells from human blood. IL-7 was found to enhance proliferation responses and IFN-gamma secretion of myelin or recall Ag-specific Th1 cells through the selective up-regulation of the IL-2Ralpha and gamma but not beta chains in both an Ag-dependent and Ag-independent manner, but did not affect monocytes, B cells, or NK cells. These functions of IL-7 enhanced the detection of Th1 but not Th2 cell frequency by2.5 fold, and promoted selection of Ag-specific Th1 cells by the limiting dilution method. Moreover, IL-7 pretreatment conferred increased resistance of CD4+ T cells to CD8+ cell lysis. These studies demonstrate that IL-7 promotes the growth and survival of circulating Ag-specific human Th1 cells through a mechanism that probably involves the gammac common receptor for IL-2 family members that includes IL-7.
- Published
- 1999
21. Induction of T cell anergy by high concentrations of immunodominant native peptide is accompanied by IL-10 production and a block in JNK activity
- Author
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Ian Robey, Carolyn N. Woody, Halina Offner, Michael P. Davey, Arthur A. Vandenbark, Yuan K. Chou, and Wei Li
- Subjects
MAP Kinase Kinase 4 ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Immunology ,Epitopes, T-Lymphocyte ,Peptide ,Biology ,Epitope ,Cell Line ,Immune system ,medicine ,Immune Tolerance ,Tetanus Toxoid ,Humans ,Aged ,chemistry.chemical_classification ,Mitogen-Activated Protein Kinase Kinases ,JNK Mitogen-Activated Protein Kinases ,Myelin Basic Protein ,Molecular biology ,Myelin basic protein ,Interleukin-10 ,Transcription Factor AP-1 ,Interleukin 10 ,Cytokine ,medicine.anatomical_structure ,chemistry ,biology.protein ,Interleukin-2 ,Female ,Protein Kinases ,Intracellular - Abstract
The ability to induce anergy in antigen-specific T cells has potential therapeutic value for altering pathologic immune responses. This study was undertaken to further analyze changes in cytokine production and intracellular signaling during anergy induction using high concentrations of native peptide ligand of tetanus toxoid (TT)- and myelin basic protein (MBP)-specific human T cell lines. The TT-selected T cell line could be rendered unresponsive to its dominant epitope in a dose-dependent manner (IC 50 = 0.03 μg/ml). The TT-selected line, as well as three T cell clones established from this line, continued to produce IFN-γ and significantly increased IL-4 and IL-10 production when anergy was induced with high concentrations of the immunodominant epitope. JNK enzymatic activity was blocked in anergized T cells. The MBP-selected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy induction was accompanied by IL-10 release. Both T cell lines could be anergized by the autopresentation of native peptide since anergy was induced in cultures lacking fresh antigen-presenting cells. This study shows that the mitogen-activated protein kinase cascade is blocked when anergy is induced to high concentrations of soluble peptide.
- Published
- 1998
22. Effects of vaccination with T cell receptor peptides: epitope switching to a possible disease-protective determinant of myelin basic protein that is cross-reactive with a TCR BV peptide
- Author
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Arthur A. Vandenbark, Ruth H. Whitham, Halina Offner, Yuan K. Chou, and Dennis Bourdette
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Epitopes, T-Lymphocyte ,Peptide ,Biology ,Cross Reactions ,Epitope ,Th2 Cells ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,IL-2 receptor ,chemistry.chemical_classification ,Experimental autoimmune encephalomyelitis ,T-cell receptor ,Vaccination ,Myelin Basic Protein ,Cell Biology ,medicine.disease ,Myelin basic protein ,Rats ,medicine.anatomical_structure ,chemistry ,biology.protein ,Peptides - Abstract
Immunization of Lewis rats with guinea-pig myelin basic protein (Gp-MBP) induced T cell responses to primary and secondary encephalitogenic determinants, as well as to a third non-encephalitogenic epitope, residues 55–69. This sequence is of interest due to its protective activity against experimental autoimmune encephalomyelitis. Protection involved induction of MBP-55–69-specific T cells expressing cross-reactive TCR BV8S6 genes that activated regulatory T cells specific for TCR BV8S2 determinants expressed on encephalitogenic T cells. We here present and discuss new evidence suggesting a possible immunological cross-reactivity between the protective Gp-MBP-55–69 peptide and the regulatory BV8S2-39–59 peptide. This cross-reactivity, which may also occur between the human MBP-55–74 peptide and the BV12S2-38–58 sequence, has potentially important implications for human diseases such as multiple sclerosis.
- Published
- 1998
23. Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial
- Author
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Ruth H. Whitham, Michele Mass, Halina Offner, Arthur A. Vandenbark, Daniel Kavanagh, Abigail C. Buenafe, Shelley A. Cooper, George A. Hashim, Diane Liefeld, Yuan K. Chou, and Dennis Bourdette
- Subjects
Adult ,Male ,Multiple Sclerosis ,Receptors, Antigen, T-Cell, alpha-beta ,Pilot Projects ,General Biochemistry, Genetics and Molecular Biology ,Autoimmune Diseases ,Double blind ,Th2 Cells ,Double-Blind Method ,T-Lymphocyte Subsets ,Medicine ,Humans ,Receptor ,Vaccines ,biology ,business.industry ,Multiple sclerosis ,Pilot trial ,T-cell receptor ,Immunotherapy, Active ,Myelin Basic Protein ,General Medicine ,HLA-DR Antigens ,Middle Aged ,medicine.disease ,In vitro ,Peptide Fragments ,Myelin basic protein ,Interleukin-10 ,Immunology ,biology.protein ,Peptide vaccine ,Disease Progression ,Female ,business ,HLA-DRB1 Chains - Abstract
A T-cell receptor (TCR) peptide vaccine from the V beta 5.2 sequence expressed in multiple sclerosis (MS) plaques and on myelin basic protein (MBP)-specific T cells boosted peptide-reactive T cells in patients with progressive MS. Vaccine responders had a reduced MBP response and remained clinically stable without side effects during one year of therapy, whereas nonresponders had an increased MBP response and progressed clinically. Peptide-specific T helper 2 cells directly inhibited MBP-specific T helper 1 cells in vitro through the release of interleukin-10, implicating a bystander suppression mechanism that holds promise for treatment of MS and other autoimmune diseases.
- Published
- 1996
24. Prevention, Suppression, and Treatment of Experimental Autoimmune Encephalomyelitis with a Synthetic T Cell Receptor V Region Peptide
- Author
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G.A. Hashim, Arthur A. Vandenbark, Dennis Bourdette, Yuan K. Chou, and Halina Offner
- Subjects
biology ,Experimental autoimmune encephalomyelitis ,T-cell receptor ,chemical and pharmacologic phenomena ,Idiotopes ,MHC restriction ,medicine.disease ,Epitope ,Immunology ,MHC class I ,medicine ,biology.protein ,Antibody ,Receptor - Abstract
Publisher Summary This chapter discusses the prevention, suppression, and treatment of experimental autoimmune encephalomyelitis with a synthetic T-cell receptor (TCR) V region peptide. The common use of TCR V β 8.2 genes by encephalitogenic, BP-specific T cells from Lewis rats has allowed the identification of a synthetic TCR sequence that can stimulate antiidiotypic regulation of the pernicious T cells. In a study described in the chapter, pre-immunication with the TCR-V β 8-39-59 peptide induced complete protection against clinical EAE by stimulating the production of specific T cells and antibodies that independently transferred protective activity. Similarly, the TCR peptide suppressed EAE when given after induction of disease, thus reducing the severity of clinical signs. However, histological lesions were evident in clinically protected rats, although T-cell responses to encephalitogenic epitopes of BP were muted. The regulatory T cells apparently recognized a processed form of the TCR expressed on the Vβ8 + T-cell surface in association with MHC class I restriction molecules to mediate regulation by noncytolytic mechanisms. It is probable that the TCR-V β 8-39-59 sequence represents a natural idiotope involved in the immunoregulation of EAE, as T cells specific for this TCR peptide were induced as a consequence of EAE in the absence of synthetic TCR-Vβ 8-39-59 peptide.
- Published
- 1993
25. Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis
- Author
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Ruth H. Whitham, Arthur A. Vandenbark, Dennis Bourdette, Run Ying Wang, Halina Offner, Yuan K. Chou, and George A. Hashim
- Subjects
Multiple Sclerosis ,T cell ,T-Lymphocytes ,Immunology ,Molecular Sequence Data ,Indicator Dilution Techniques ,Biology ,Myelin ,Leukocyte Count ,Cerebrospinal fluid ,Antigen ,medicine ,Immunology and Allergy ,Humans ,Amino Acid Sequence ,Amino Acids ,Myelin Proteolipid Protein ,Cerebrospinal Fluid ,Blood Cells ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Myelin Basic Protein ,medicine.disease ,Myelin basic protein ,Myelin proteolipid protein ,medicine.anatomical_structure ,Neurology ,biology.protein ,Interleukin-2 ,Neurology (clinical) ,Interleukin-4 ,Myelin Proteins - Abstract
T cell sensitization to two myelin components, myelin basic protein (MBP) and myelin proteolipid protein (PLP), may be important to the pathogenesis of multiple sclerosis (MS). Using the limiting dilution assay, we demonstrated that the blood of MS patients had an increased frequency of MBP-reactive T cells compared with normal subjects and patients with other neurological diseases (OND) and rheumatoid arthritis. There was no difference in T cell frequency to a synthetic peptide, PLP 139−151 , or Herpes simplex virus. Within cerebrospinal fluid (CSF), 37% of IL-2/IL-4-reactive T cell isolates from MS patients responded either to MBP or PLP 139−151 while only 5% of similar isolates from OND patients responded to these myelin antigens. The mean relative frequency of MBP-reactive T cells within CSF from MS patients was significantly higher than that of OND patients (22 × 10 −5 cell versus 1 × 10 −5 cells) and was similar to that of MBP reactive T cells within the central nervous system of rats with experimental autoimmune encephalomyelitis. These results lend new support to the hypothesis that myelin-reactive T cells mediate disease in MS.
- Published
- 1992
26. T cell receptor peptide therapy for autoimmune disease
- Author
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Dennis N. Bourdette, G.A. Hashim, Halina Offner, Arthur A. Vandenbark, Yuan K. Chou, and Ruth Whitham
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T cell ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,medicine.disease_cause ,Autoimmunity ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,IL-2 receptor ,Autoimmune disease ,Immunity, Cellular ,biology ,Experimental autoimmune encephalomyelitis ,T-cell receptor ,medicine.disease ,Peptide Fragments ,Rats ,medicine.anatomical_structure ,Rats, Inbred Lew ,Antibody Formation ,biology.protein ,Antibody - Abstract
Synthetic peptides corresponding to germline T cell receptor (TCR) Vβ08260 sequences shared by encephalitogenic T cells can prevent and treat experimental autoimmune encephalomyelitis in rats. The operative mechanism apparently involves boosting of anti-TCR immunity that develops during the course of experimental autoimmune encephalomyelitis (EAE), leading to the induction of autoregulatory T cells and antibodies. Striking parallels are present between patients with multiple sclerosis and animals with EAE in the T cell frequency and TCR V gene bias of BP reactive T cells, suggesting the involvement of an encephalitogenic process in multiple sclerosis. Preliminary trials with the appropriate human TCR peptides indicate that anti-TCR immunity can be boosted efficiently and safely, with concomitant loss of BP response, thus providing an effective strategy for selective regulation of autoimmunity in man.
- Published
- 1992
27. Yeast product supplementation modulated humoral and mucosal immunity and uterine inflammatory signals in transition dairy cows.
- Author
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Yuan, K., Mendonça, L. G. D., Hulbert, L. E., Mamedova, L. K., Muckey, M. B., Shen, Y., Elrod, C. C., and Bradford, B. J.
- Subjects
- *
YEAST research , *EDIBLE fungi , *LEAVENING agents , *IMMUNITY , *IMMUNOLOGY - Abstract
The transition from late gestation to early lactation is characterized by substantial metabolic stress and altered immune function. The objective of this study was to assess the effects of supplementing a yeast product derived from Saccharomyces cerevisiae on immunity and uterine inflammation in transition cows. Forty multiparous Holstein cows were blocked by expected parturition date and randomly assigned within block to 1 of 4 treatments (n = 10) from 21 d before expected parturition to 42 d postpartum. Rations were top-dressed with a product containing yeast culture plus enzymatically hydrolyzed yeast (YC-EHY; Celmanax, Vi-COR, Mason City, IA) at the rate of 0, 30, 60, or 90 g/d throughout the experiment. Cows were injected subcutaneously with ovalbumin on d -21, -7, and 14 to assess their humoral response. Data were analyzed using mixed models with repeated measures over time. Concentrations of colostrum IgG were unaffected by treatments. A treatment x week interaction was observed for somatic cell linear score, reflecting a tendency for a quadratic dose effect on wk 1 (2.34, 2.85, 1.47, and 4.06 ± 0.59 for 0, 30, 60, and 90 g/d, respectively) and a quadratic dose effect on wk 5 (1.36, -0.15, -1.07, and 0.35 ± 0.64 for 0, 30, 60, and 90 g/d, respectively). Platelet count was increased by YC-EHY. Increasing YC-EHY dose linearly increased plasma anti-ovalbumin IgG levels following 3 ovalbumin challenges, suggesting that treatments enhanced humoral immunity. Increasing YC-EHY dose also quadratically increased fecal IgA concentrations in early lactation, suggesting that 30 and 60 g/d doses enhanced mucosal immunity. Uterine neutrophil populations were much greater in samples collected on d 7 compared with those on d 42 (32.1 vs. 7.6 ± 3.5% of cells), reflecting neutrophil infiltration immediately after calving, but no treatment effect was detected. Significant day effects were detected for mRNA of IL-6, IL-8, neutrophil myeloperoxidase (MPO), and neutrophil elastase (ELANE) in the uterine samples, reflecting greater abundance of these transcripts collected on d 7 compared with d 42. A quadratic dose effect was detected for IL-6, indicating that 30 and 60 g/d doses decreased uterine IL-6 mRNA. The mRNA abundance of MPO and ELANE was increased linearly by YC-EHY. Supplementation with YC-EHY enhanced measures of humoral and mucosal immunity and modulated uterine inflammatory signals and mammary gland health in transition dairy cows. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
28. Erratum to 'αB-Crystallin-reactive T cells from knockout mice are not encephalitogenic' [J. Neuroimmunol. 176 (2006) 51–62]
- Author
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Halina Offner, Jason M. Link, Cathleen Rich, Eric F. Wawrousek, Yuan K. Chou, Michael Afentoulis, Johannes M. van Noort, Chunhe Wang, and Arthur A. Vandenbark
- Subjects
medicine.medical_specialty ,business.industry ,αb crystallin ,Immunology ,humanities ,Neurology ,Anesthesiology ,Family medicine ,Knockout mouse ,Immunology and Allergy ,Medicine ,Neurology (clinical) ,business ,Veterans Affairs ,health care economics and organizations - Abstract
a Neuroimmunology Research, Veterans Affairs Medical Center, Portland, 97239 OR, USA b Department of Neurology, Oregon Health and Science University, USA c Division of Immunological and Infectious Diseases, TNO Prevention and Health, PO Box 2215, 2301 CE Leiden, The Netherlands d National Eye Institute, National Institutes of Health, Bethesda, 20892 MD, USA e Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, USA f Department of Molecular Microbiology and Immunology, Oregon Health and Science University, USA
- Published
- 2008
29. Suppressor cell regulation of encephalitogenic T cell lines: generation of suppressor macrophages with cyclosporin A and myelin basic protein
- Author
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Arthur A. Vandenbark, Halina Offner, Yuan K. Chou, Dennis Bourdette, and Ruth H. Whitham
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,T cell ,Immunology ,Cyclosporins ,Lymphocyte Activation ,Tuberculin ,T-Lymphocytes, Regulatory ,Cell Line ,Mice ,Antigen ,Cyclosporin a ,Splenocyte ,medicine ,Animals ,biology ,Cell growth ,Macrophages ,Myelin Basic Protein ,Molecular biology ,Myelin basic protein ,medicine.anatomical_structure ,Cell culture ,Antigens, Surface ,Myeloid-derived Suppressor Cell ,biology.protein ,Thy-1 Antigens ,Female - Abstract
Chronic relapsing experimental allergic encephalomyelitis (CR-EAE) can be adoptively transferred using myelin basic protein (BP)-specific helper T cell lines, and suppressor cells may be important in recovery from EAE. In order to generate suppressor cells, spleen cells obtained from BP-complete Freund's adjuvant (CFA) inoculated SJL/J mice and from normal mice were cultured for 7 days with medium, with cyclosporin A (CsA), or with CsA and antigen (BP or purified protein derivative of mycobacterium (PPD)). Cultured spleen cells were assayed for suppressor activity in vitro by coculture with BP-specific and PPD-specific helper T cell lines derived from SJL/J mice. Immunized donor spleen cells cultured with cyclosporin A (CsA) and BP were potent inhibitors of T cell line proliferation, and suppressor activity was increased 17-fold compared with control splenocytes. The number of suppressor cells required to suppress PPD-specific line proliferation by 50% ( I 50 ) was significantly higher than the number required to suppress BP-specific line proliferation, suggesting an antigen-specific component to the suppression. The major effector cell required for suppression was a large granular Mac-1 + cell with the functional characteristics of a macrophage. Suppressor activity persisted after depletion of Thy 1.2+ cells, but suppression was no longer antigen-specific, suggesting that culture of spleen cells with CsA and BP may generate suppressor macrophages which are antigen-nonspecific and Thy 1.2+ suppressor cells which are antigen-specific. These suppressor cells may be important in the regulation of CR-EAE and the techniques described for their generation may prove useful for treatment and prevention of disease.
- Published
- 1990
30. Immunity to T cell receptor peptides in multiple sclerosis. III. Preferential immunogenicity of complementarity determi4ning region 2 peptides from disease-associated TCR BV
- Author
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Abigail C. Buenafe, S.A. Cooper, Jane H. Buckner, Yuan K. Chou, Gerald T. Nepom, Halina Offner, A A Vandenbark, Dennis Bourdette, Mark Allegretta, and R.H. Whitman
- Subjects
Multiple sclerosis ,Immunogenicity ,Immunology ,T-cell receptor ,Disease ,Biology ,medicine.disease ,Virology ,Neurology ,Immunity ,Complementarity (molecular biology) ,medicine ,Immunology and Allergy ,Neurology (clinical) - Published
- 1998
31. TCR peptide-specific human TH2 cells inhibit BP-specific TH1 effector cells
- Author
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Yuan K. Chou, AA Vandenbark, and H Offner
- Subjects
chemistry.chemical_classification ,CD40 ,biology ,Effector ,Chemistry ,Immunology ,T-cell receptor ,Peptide ,Cell biology ,Neurology ,Interleukin 12 ,biology.protein ,Immunology and Allergy ,Neurology (clinical) ,IL-2 receptor ,Interleukin 3 - Published
- 1995
32. Characterization of TCR peptide-specific T cells from MS patients
- Author
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Halina Offner, Andrew D. Weinberg, Dennis Bourdette, Yuan K. Chou, Ruth H. Whitham, and A A Vandenbark
- Subjects
chemistry.chemical_classification ,Neurology ,Chemistry ,Immunology ,T-cell receptor ,Immunology and Allergy ,Peptide ,Neurology (clinical) ,Molecular biology - Published
- 1994
33. Successful immunization of multiple sclerosis patients with synthetic TCR Vβ peptides
- Author
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G.A. Hashim, Yuan K. Chou, A. Buenefe, A A Vandenbark, Ruth H. Whitham, Halina Offner, and Dennis Bourdette
- Subjects
Neurology ,Immunization ,business.industry ,Multiple sclerosis ,Immunology ,Immunology and Allergy ,Medicine ,Neurology (clinical) ,business ,medicine.disease - Published
- 1994
34. TCR peptide therapy regulates basic protein specific T cell frequency in patients with multiple sclerosis
- Author
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G.A. Hashim, Ruth H. Whitham, Yuan K. Chou, Halina Offner, A A Vandenbark, and Dennis Bourdette
- Subjects
chemistry.chemical_classification ,business.industry ,Multiple sclerosis ,T cell ,Immunology ,T-cell receptor ,Peptide ,medicine.disease ,medicine.anatomical_structure ,Neurology ,chemistry ,Cancer research ,Immunology and Allergy ,Medicine ,In patient ,Neurology (clinical) ,business - Published
- 1991
35. Human T lymphocyte response to myelin basic protein: Selection of T lymphocyte lines from mbp-responsive donors
- Author
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M. Vainiene, Halina Offner, Arthur A. Vandenbark, G.A. Hashim, Ruth H. Whitham, Dennis Bourdette, C. H.-J. Chou, J. Chilgren, Yuan K. Chou, and G. Konat
- Subjects
Adult ,Male ,Cellular immunity ,Multiple Sclerosis ,T-Lymphocytes ,T cell ,Immunoblotting ,Biology ,Lymphocyte Activation ,Epitope ,Cell Line ,Cellular and Molecular Neuroscience ,Myelin ,Immune system ,Reference Values ,medicine ,Humans ,Cells, Cultured ,Multiple sclerosis ,Myelin Basic Protein ,T lymphocyte ,Middle Aged ,medicine.disease ,Myelin basic protein ,Molecular Weight ,medicine.anatomical_structure ,Immunology ,biology.protein ,Female - Abstract
The goal of this study was to delineate the importance of blood T lymphocyte responses to several myelin basic protein (MBP) preparations in the ultimate selection of MBP-specific T lymphocyte lines. Proliferation responses to human myelin basic protein (MBP) were assessed in blood samples from 27 multiple sclerosis (MS) patients, 20 patients with other neurologic diseases (OND), and 26 normal subjects, using five MBP preparations with different histories and electrophoretic characteristics to enhance the spectrum of epitopes represented. Substantial variations were observed in the ability of different MBP preparations to induce blood T cell proliferation in a given donor. However, four out of five of the MBPs induced modest but significant proliferation in the MS study population relative to normal individuals, with intermediate responses occurring in OND patients. Positive responses occurred more frequently in MS patients (78%) than in normal donors (31%), and were an important prerequisite for the successful selection of MBP-specific T cell lines.
- Published
- 1989
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