T-Cell Vaccination

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J. Raus - One of the best experts on this subject based on the ideXlab platform.

  • Long-term effects of T cell Vaccination in multiple sclerosis
    Treatment of Autoimmune Disorders, 2020
    Co-Authors: Piet Stinissen, Robert Medaer, Guy Hermans, Niels Hellings, J. Raus
    Abstract:

    Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterised by focal areas of demyelination in the CNS (Ffrench-Constant 1994). Autoimmune processes involving myelin-reactive T cells are considered to play an essential role in the pathogenesis of MS (for a review, see Stinissen et al. 1997). In vivo activated T cells reactive to myelin basic protein (MBP) are clonally expanded in the blood of MS patients and may persist for many years in some patients (Goebels et al. 2000). The activation of MBP-reactive T cells via molecular mimicry could be a common process, as suggested by the high level of cross-reactivity of MBP-reactive T cells to various microbial ligands, even in the absence of any sequence homology (Wucherpfennig et al. 1995,Hemmer et al. 1998). Accidentally stimulated autoreactive T cells however may not automatically lead to autoimmunity. Indeed, several observations support the existence of a peripheral regulatory network that prevents activation or expansion of pathogenic T cells (Cohen et al. 1992). However, an imbalanced regulatory network may lead to sub-optimal suppression of activated pathogenic T cells and give rise to autoimmunity. Administration of attenuated autoreactive T cells as a vaccine (T cell Vaccination, TCV) may enhance the regulatory networks to specifically suppress the eliciting autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (Ben-Nun et al. 1981,Lider et al. 1988). We have performed a pilot study of TCV with MBP-reactive T cells in a small number of MS patients (Zhang et al. 1993,Medaer et al. 1995). The patients were immunised three times with autologous irradiated MBP-reactive T cell clones (see Figure 1).

  • T-Cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-Cell Vaccination.
    Expert Review of Clinical Immunology, 2006
    Co-Authors: Niels Hellings, J. Raus, Piet Stinissen
    Abstract:

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-Cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-Cell Vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-Cell Vaccination has b...

  • T-Cell Vaccination in multiple sclerosis: update on clinical application and mode of action.
    Autoimmunity Reviews, 2003
    Co-Authors: Niels Hellings, J. Raus, Piet Stinissen
    Abstract:

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Autoreactive T cells specific for myelin antigens are considered to play a prominent role in the initiation of the local inflammatory response, ultimately leading to myelin damage. Several studies indicate that autoreactive T cells are not completely deleted in the thymus, but are part of the normal T cell repertoire. Accidentally activated autoreactive T cells, however, may not automatically lead to autoimmune disease. Several reports support the existence of peripheral regulatory networks that prevent the activation and expansion of pathogenic T cells. Anti-idiotypic and anti-ergotypic T cells are part of this regulatory network and are thought to control autoreactive T cells by recognition of certain clonotypic and ergotypic determinants. These clonotypic networks may not function properly in patients with MS. Immunization with attenuated autoreactive T cells, termed T cell Vaccination (TCV), may enhance or restore the regulatory networks to specifically suppress the autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model for MS. In the past decade, TCV has been tested for MS in several clinical trails. This review summarizes these clinical trails and updates our current knowledge on the mode of action of T cell Vaccination.

  • Myelin reactive T cells after T cell Vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations
    Journal of Neuroimmunology, 2000
    Co-Authors: Guy Hermans, J. Raus, Robert Medaer, Piet Stinissen
    Abstract:

    Abstract Pathogenic autoreactive T cells can be targeted by T cell Vaccination (TCV), a procedure in which patients are immunized with autologous attenuated pathogenic T cells. We reported previously that TCV with myelin basic protein (MBP) reactive T cell clones in multiple sclerosis (MS) patients induced T cell immune responses, resulting in a clonal depletion of MBP reactive T cells in all patients. Five years after TCV, MBP reactive T cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before Vaccination. We have studied the cytokine profile, cytotoxicity and epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a pathogenic role in the disease. We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T cell targeted immunotherapies for MS and other autoimmune diseases.

  • Cellular and humoral immune responses against autoreactive T cells in multiple sclerosis patients after T cell Vaccination.
    Journal of Autoimmunity, 1999
    Co-Authors: Guy Hermans, J. Raus, Ansgar W. Lohse, Ulrike Denzer, Piet Stinissen
    Abstract:

    Abstract Myelin basic protein (MBP)-reactive T cells may play an important role in the autoimmune pathogenesis of multiple sclerosis (MS). MBP-reactive T cells can be specifically targeted by T cell Vaccination, a procedure whereby MS patients are immunized with attenuated autologous MBP reactive T cells. T cell Vaccination induces immune responses to the vaccine cells together with a depletion of MBP reactive T cells. Forty-nine MS patients were treated with T cell Vaccination in an extended phase I trial to study the safety, immune responses and clinical effects of T cell Vaccination. In the present paper the immune responses towards the vaccine cells were characterized. Substantial long-term in vitro proliferative responses were observed in all treated patients. Some patients, immunized with different clones, displayed distinct proliferative reactivity against the various vaccine clones, suggesting unequal immunogenic properties of these clones. Reactive TCRαβ + , CD8 + and CD4 + T cells, and to a lesser extent, γδ T cells and NK cells were observed to in vitro stimulation with the vaccine cells. A small fraction only of CD8 + T cells expressed cytolytic and inhibitory anti-clonotypic reactivity against the vaccine cells. Stimulation with the vaccine clones predominantly induced expression of pro-inflammatory cytokines in these mixed cultures, although one vaccine clone consistently induced production of IL-4. CD4 + T cells are the major cytokine-producing cells in these anti-vaccine lines. We could not detect upregulated antibody responses to the vaccine cells in most patients, although a temporary antibody response was observed in one patient. In conclusion, immunization with attenuated autoreactive T cells induces a complex cellular response specifically targeted at the vaccine cells, but no antibody responses. These data provide further insights into the mechanisms of T cell Vaccination and improve our understanding of the complex regulatory networks of autoreactive T cells.

Jingwu Z. Zhang - One of the best experts on this subject based on the ideXlab platform.

  • T-Cell Vaccination in multiple sclerosis: immunoregulatory mechanism and prospects for therapy.
    Critical Reviews in Immunology, 2020
    Co-Authors: Jingwu Z. Zhang
    Abstract:

    : Vaccination with inactivated autoreactive T cells (T-Cell Vaccination) was originally developed to study immune regulation in experimental autoimmune conditions. During the last two decades, research in this area has led to the new understanding of cellular and molecular mechanisms whereby autoreactive T cells are regulated in vivo and the development of new therapeutic strategies using synthetic peptides and plasmid or viral DNA vectors. Recently T-Cell Vaccination has been advanced to human trials in patients with multiple sclerosis. These early clinical studies were designed to test the potential treatment efficacy of T-Cell Vaccination and have shown some promising results. In this article, new insights in the understanding of the regulatory mechanism induced by T-Cell Vaccination and the results of the clinical trials are reviewed. In particular, issues related to the improvement of the current T-Cell Vaccination protocol are discussed in relationship to the concept of immune regulation and clinical considerations.

  • CD4+ regulatory T cell responses induced by T cell Vaccination in patients with multiple sclerosis
    Proceedings of the National Academy of Sciences of the United States of America, 2006
    Co-Authors: Jian Hong, Ying C. Q. Zang, Jingwu Z. Zhang
    Abstract:

    Immunization with irradiated autologous T cells (T cell Vaccination) is shown to induce regulatory T cell responses that are poorly understood. In this study, CD4+ regulatory T cell lines were generated from patients with multiple sclerosis that received immunization with irradiated autologous myelin basic protein-reactive T cells. The resulting CD4+ regulatory T cell lines had marked inhibition on autologous myelin basic protein-reactive T cells and displayed two distinctive patterns distinguishable by the expression of transcription factor Foxp3 and cytokine profile. The majority of the T cell lines had high Foxp3 expression and secreted both IFN-γ and IL-10 as compared with the other pattern characteristic of low Foxp3 expression and predominant production of IL-10 but not IFN-γ. CD4+ regulatory T cell lines of both patterns expressed CD25 and reacted with activated autologous T cells but not resting T cells, irrespective of antigen specificity of the target T cells. It was evident that they recognized preferentially a synthetic peptide corresponding to residues 61–73 of the IL-2 receptor α chain. T cell Vaccination correlated with increased Foxp3 expression and T cell reactivity to peptide 61–73. The findings have important implications in the understanding of the role of CD4+ regulatory T cell response induced by T cell Vaccination.

  • T Cell Vaccination as an Immunotherapy for Autoimmune Diseases
    Cellular & Molecular Immunology, 2004
    Co-Authors: Jingwu Z. Zhang
    Abstract:

    : Immunization with inactivated autoreactive T cells (T cell Vaccination) selected from individual's own T cell repertoire provides a unique in vivo setting for testing immune regulation that is known to involve interactions of a variety of related surface molecules (1). It induces regulatory immune responses that closely resemble the in vivo situation where the immune system is challenged by clonal activation and expansion of given T cell populations in various autoimmune diseases. T cell Vaccination provides a powerful means of eliciting natural reactions of the immune system in response to clonal expansion of T cells, which can be used as a therapeutic approach to suppress or eliminate specific pathogenic autoreactive T cells in autoimmune conditions. Clinical trials using T cell Vaccination to deplete autoreactive T cells in human autoimmune conditions have begun to reveal the pathologic relevance of various autoimmune T cell populations in the disease processes, providing a unique opportunity to test the autoimmune theories in a clinical setting.

  • T cell Vaccination in multiple sclerosis: results of a preliminary study.
    Journal of Neurology, 2002
    Co-Authors: Jingwu Z. Zhang, Jian Hong, Maria V. Tejada-simon, Victor M. Rivera, James M. Killian, Deye Yang, Sufanfg Li, Hani Haykal, Ying C. Q. Zang
    Abstract:

    Myelin basic protein (MBP)-reactive T cells are potentially involved in the pathogenesis of multiple sclerosis (MS), and can be depleted by subcutaneous inoculations with irradiated autologous MBP-reactive T cells (T cell Vaccination). This preliminary open label study was undertaken to evaluate whether depletion of MBP-reactive T cells would be clinically beneficial to patients with MS. Fifty-four patients with relapsing-remitting (RR) MS (n=28) or secondary progressive (SP) MS (n=26) were immunized with irradiated autologous MBP-reactive T cells and monitored for changes in rate of relapse, expanded disability scale score (EDSS) and MRI lesion activity over a period of 24 months. Depletion of MBP-reactive T cells correlated with a reduction (40 %) in rate of relapse in RR-MS patients as compared with the pre-treatment rate in the same cohort. However, the reduction in EDSS was minimal in RR-MS patients while the EDSS was slightly increased in SP-MS patients over a period of 24 months. Serial semi-quantitative MRI examinations suggest stabilization in lesion activity as compared with baseline MRI. The findings suggest some potential clinical benefit of T cell Vaccination in MS and encourage further investigations to evaluate the treatment efficacy of T cell Vaccination in controlled trials.

  • T cell Vaccination from basics to the clinic
    Trends in Immunology, 2001
    Co-Authors: Vipin Kumar, Jingwu Z. Zhang, Eli E. Sercarz, Irun R. Cohen
    Abstract:

    References 1 Pap, T. et al. (2000) Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2, 361–367 2 van der Laan, W.H. et al. (2000) Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cellsurface-targeted plasmin inhibitor. Arthritis Rheum. 43, 1710–1718 3 Mountz, J.D. et al. (2001) Apoptosis and rheumatoid arthritis: past, present and future directions. Curr. Rheumatol. Rep. 3, 70–78 4 Lubberts, E. et al. (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J. Immunol. 167, 1004–1013 5 Watanabe, S. et al. (2000) Adeno-associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium. Mol. Ther. 2, 147–152 6 Douar, A.M. et al. (2001) Intracellular trafficking of adeno-associated virus vectors: routing to the late endosomal compartment and proteasome degradation. J. Virol. 75, 1824–1833 7 Ghivizzani, S.C. et al. (2001) Direct gene delivery strategies for the treatment of rheumatoid arthritis. Drug Discov. Today 6, 259–267 8 Peterson, L. et al. (2000) Twoto 9-year outcome after autologous chondrocyte transplantation of the knee. Clin. Orthop. 374, 212–234 9 Lisignoli, G. et al. (2001) Basic fibroblast growth factor enhances in vitro mineralization of rat bone marrow stromal cells grown on nonwoven hyaluronic-acid-based polymer scaffold. Biomaterials 22, 2095–2105 10 Turgeman, G. et al. (2001) Engineered human mesenchymal stem cells: a novel platform for skeletal-cell-mediated gene therapy. J. Gene Med. 3, 240–251 11 Moutsatsos, I.K. et al. (2001) Exogenously regulated stem-cell-mediated gene therapy for bone regeneration. Mol. Ther. 3, 449–461

Irun R. Cohen - One of the best experts on this subject based on the ideXlab platform.

  • T-Cell Vaccination against anti-CD4 autoimmunity in HIV-1 infected patients.
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 2020
    Co-Authors: Rivka Abulafia-lapid, Yael Keren-zur, Irun R. Cohen, Zvi Bentwich, Henri Atlan
    Abstract:

    Highly active antiretroviral therapy (HAART) is frequently associated with only partial restoration of CD4 T-Cell levels. Autoimmunity to CD4 T-Cells may account for the persistence of the CD4 T-Cell lymphopenia in such cases. To document T-Cell autoimmunity to CD4 in HIV-infected patients and to determine if T-Cell Vaccination against CD4 autoimmunity is feasible and safe. Seven out of 20 HIV-infected patients undergoing HAART who manifested T- cell reactivity to rCD4, gp120 and to recall antigens (Tetanus toxoid and Candida) were treated with T-Cell vaccines composed of glutaraldehyde treated autologous, activated T-Cells, and enriched in anti CD4-reactive T-Cells. The response of the seven vaccinated patients was compared to seven non-vaccinated HIV-1 infected subjects. Five out of seven responded with a decrease in anti-CD4 autoimmunity, associated with a persistent increase in their CD4 T-Cell levels; just one of the control patients showed increased CD4 levels. No change in HIV plasma viral loads and no adverse effects were detected in any of the T-Cell vaccinated patients. The persistence of CD4 T-Cell lymphopenia despite effective anti-retroviral treatment may be associated with anti-CD4 autoimmunity. T-Cell Vaccination with autologous autoimmune CD8 T-Cells may decrease such autoimmunity and increase CD4 T-Cell numbers.

  • T-Cell Vaccination: An Insight Into T-Cell Regulation
    Translational Neuroimmunology in Multiple Sclerosis, 2016
    Co-Authors: Irun R. Cohen, Nir Friedman, Francisco J. Quintana
    Abstract:

    Here we review T-Cell Vaccination (TCV), a cell-based, generic approach to immune regulation. We describe TCV clinical trials in multiple sclerosis and other autoimmune diseases; we analyze the immune regulatory mechanisms activated by TCV; we examine the potential of public T cells as TCV mediators, and we discuss the physiology of immune regulation in the light of TCV.

  • T cell Vaccination induces the elimination of EAE effector T cells: analysis using GFP-transduced, encephalitogenic T cells.
    Journal of Autoimmunity, 2010
    Co-Authors: Ilan Volovitz, Yotvat Marmor, Alexander Flügel, Francesca Odoardi, Lea Eisenbach, Irun R. Cohen
    Abstract:

    Abstract T cell Vaccination (TCV) with irradiated encephalitogenic T cells induces resistance to EAE. However, the fate of the encephalitogenic T cells in vivo following TCV has yet to be studied. Here we used anti-MBP encephalitogenic T cells that were transduced to express GFP to study the effects of TCV on these cells. In naive rats or in control-vaccinated (Ova-GFP) rats injected i.v. with GFP-labeled effector cells, high numbers of effector T cells were found along with macrophages, CD8 T cells and Non-GFP CD4 cells in the spleens, parathymic lymph nodes (PTLN) and spinal cords. In contrast, the recipients that had been treated with TCV (anti-MBP T-Cell lines) showed few if any GFP-labeled effector T cells throughout the disease (day 1–8) and their spinal cords were almost clear of macrophages, CD4 and CD8 cells. Splenocytes in the control groups secreted IFNγ in response to MBP and showed high numbers of IFNγ secreting CD4 and CD8 cells in their spinal cords at the disease peak. In the TCV-protected groups, splenocytes showed no reactivity to MBP but secreted IFNγ in response to irradiated encephalitogenic T cells – an anti-idiotypic response. Thus, TCV leads to a marked decrease in the numbers of effector T cells in the CNS and lymphoid organs, to a marked reduction in the Th1 cytokine producing cells in the CNS, and to the appearance of T cells responsive to the anti-MBP effector T cells.

  • T-Cell Vaccination against anti-CD4 autoimmunity in HIV-1 subtypes B and C-infected patients--an extended open trial.
    Vaccine, 2005
    Co-Authors: Rivka Abulafia-lapid, Irun R. Cohen, Yael Keren-zur, Zvi Bentwich, Shlomo Mayan, Yulia Avbramovitz, Henri Atlan
    Abstract:

    This study is an extended clinical trial of the one initiated and reported in the Journal of Clinical Virology 2004;31S:S48-54. Thirteen HIV-1 patients (eight subtype B and five subtype C) that manifested T-Cell autoimmunity to recombinant human CD4 (rCD4) were treated with T-Cell vaccine composed of glutaraldehyde-treated autologous anti-CD4 reactive T-Cells and compared to historical seven non-vaccinated HIV-1-infected subjects. This study proved to be feasible and safe. Follow-up study revealed that 7/8 subtype B and 2/4 subtype C patients (one has just received the first TCV injection) responded with a persistent increase in their blood CD4 T-Cell levels and four subtype B patients manifested decreased anti-CD4 autoimmunity. Despite highly active antiretroviral therapy (HAART), the persistence of CD4 T-Cell lymphopenia may be associated with anti-CD4 autoimmunity. T-Cell Vaccination (TCV) may decrease such autoimmunity and elevate CD4 T-Cell numbers.

  • T-Cell Vaccination against anti-CD4 autoimmunity in HIV-1 infected patients.
    Journal of Clinical Virology, 2004
    Co-Authors: Rivka Abulafia-lapid, Yael Keren-zur, Irun R. Cohen, Zvi Bentwich, Henri Atlan
    Abstract:

    Abstract Background: Highly active antiretroviral therapy (HAART) is frequently associated with only partial restoration of CD4 T-Cell levels. Autoimmunity to CD4 T-Cells may account for the persistence of the CD4 T-Cell lymphopenia in such cases. Objective: To document T-Cell autoimmunity to CD4 in HIV-infected patients and to determine if T-Cell Vaccination against CD4 autoimmunity is feasible and safe. Study design: Seven out of 20 HIV-infected patients undergoing HAART who manifested T- cell reactivity to rCD4, gp120 and to recall antigens (Tetanus toxoid and Candida) were treated with T-Cell vaccines composed of glutaraldehyde treated autologous, activated T-Cells, and enriched in anti CD4-reactive T-Cells. The response of the seven vaccinated patients was compared to seven non-vaccinated HIV-1 infected subjects. Results: Five out of seven responded with a decrease in anti-CD4 autoimmunity, associated with a persistent increase in their CD4 T-Cell levels; just one of the control patients showed increased CD4 levels. No change in HIV plasma viral loads and no adverse effects were detected in any of the T-Cell vaccinated patients. Conclusions: The persistence of CD4 T-Cell lymphopenia despite effective anti-retroviral treatment may be associated with anti-CD4 autoimmunity. T-Cell Vaccination with autologous autoimmune CD8 T-Cells may decrease such autoimmunity and increase CD4 T-Cell numbers.

Piet Stinissen - One of the best experts on this subject based on the ideXlab platform.

  • Long-term effects of T cell Vaccination in multiple sclerosis
    Treatment of Autoimmune Disorders, 2020
    Co-Authors: Piet Stinissen, Robert Medaer, Guy Hermans, Niels Hellings, J. Raus
    Abstract:

    Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterised by focal areas of demyelination in the CNS (Ffrench-Constant 1994). Autoimmune processes involving myelin-reactive T cells are considered to play an essential role in the pathogenesis of MS (for a review, see Stinissen et al. 1997). In vivo activated T cells reactive to myelin basic protein (MBP) are clonally expanded in the blood of MS patients and may persist for many years in some patients (Goebels et al. 2000). The activation of MBP-reactive T cells via molecular mimicry could be a common process, as suggested by the high level of cross-reactivity of MBP-reactive T cells to various microbial ligands, even in the absence of any sequence homology (Wucherpfennig et al. 1995,Hemmer et al. 1998). Accidentally stimulated autoreactive T cells however may not automatically lead to autoimmunity. Indeed, several observations support the existence of a peripheral regulatory network that prevents activation or expansion of pathogenic T cells (Cohen et al. 1992). However, an imbalanced regulatory network may lead to sub-optimal suppression of activated pathogenic T cells and give rise to autoimmunity. Administration of attenuated autoreactive T cells as a vaccine (T cell Vaccination, TCV) may enhance the regulatory networks to specifically suppress the eliciting autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (Ben-Nun et al. 1981,Lider et al. 1988). We have performed a pilot study of TCV with MBP-reactive T cells in a small number of MS patients (Zhang et al. 1993,Medaer et al. 1995). The patients were immunised three times with autologous irradiated MBP-reactive T cell clones (see Figure 1).

  • T-Cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-Cell Vaccination.
    Expert Review of Clinical Immunology, 2006
    Co-Authors: Niels Hellings, J. Raus, Piet Stinissen
    Abstract:

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-Cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-Cell Vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-Cell Vaccination has b...

  • T-Cell Vaccination in multiple sclerosis: update on clinical application and mode of action.
    Autoimmunity Reviews, 2003
    Co-Authors: Niels Hellings, J. Raus, Piet Stinissen
    Abstract:

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Autoreactive T cells specific for myelin antigens are considered to play a prominent role in the initiation of the local inflammatory response, ultimately leading to myelin damage. Several studies indicate that autoreactive T cells are not completely deleted in the thymus, but are part of the normal T cell repertoire. Accidentally activated autoreactive T cells, however, may not automatically lead to autoimmune disease. Several reports support the existence of peripheral regulatory networks that prevent the activation and expansion of pathogenic T cells. Anti-idiotypic and anti-ergotypic T cells are part of this regulatory network and are thought to control autoreactive T cells by recognition of certain clonotypic and ergotypic determinants. These clonotypic networks may not function properly in patients with MS. Immunization with attenuated autoreactive T cells, termed T cell Vaccination (TCV), may enhance or restore the regulatory networks to specifically suppress the autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model for MS. In the past decade, TCV has been tested for MS in several clinical trails. This review summarizes these clinical trails and updates our current knowledge on the mode of action of T cell Vaccination.

  • Myelin reactive T cells after T cell Vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations
    Journal of Neuroimmunology, 2000
    Co-Authors: Guy Hermans, J. Raus, Robert Medaer, Piet Stinissen
    Abstract:

    Abstract Pathogenic autoreactive T cells can be targeted by T cell Vaccination (TCV), a procedure in which patients are immunized with autologous attenuated pathogenic T cells. We reported previously that TCV with myelin basic protein (MBP) reactive T cell clones in multiple sclerosis (MS) patients induced T cell immune responses, resulting in a clonal depletion of MBP reactive T cells in all patients. Five years after TCV, MBP reactive T cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before Vaccination. We have studied the cytokine profile, cytotoxicity and epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a pathogenic role in the disease. We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T cell targeted immunotherapies for MS and other autoimmune diseases.

  • Cellular and humoral immune responses against autoreactive T cells in multiple sclerosis patients after T cell Vaccination.
    Journal of Autoimmunity, 1999
    Co-Authors: Guy Hermans, J. Raus, Ansgar W. Lohse, Ulrike Denzer, Piet Stinissen
    Abstract:

    Abstract Myelin basic protein (MBP)-reactive T cells may play an important role in the autoimmune pathogenesis of multiple sclerosis (MS). MBP-reactive T cells can be specifically targeted by T cell Vaccination, a procedure whereby MS patients are immunized with attenuated autologous MBP reactive T cells. T cell Vaccination induces immune responses to the vaccine cells together with a depletion of MBP reactive T cells. Forty-nine MS patients were treated with T cell Vaccination in an extended phase I trial to study the safety, immune responses and clinical effects of T cell Vaccination. In the present paper the immune responses towards the vaccine cells were characterized. Substantial long-term in vitro proliferative responses were observed in all treated patients. Some patients, immunized with different clones, displayed distinct proliferative reactivity against the various vaccine clones, suggesting unequal immunogenic properties of these clones. Reactive TCRαβ + , CD8 + and CD4 + T cells, and to a lesser extent, γδ T cells and NK cells were observed to in vitro stimulation with the vaccine cells. A small fraction only of CD8 + T cells expressed cytolytic and inhibitory anti-clonotypic reactivity against the vaccine cells. Stimulation with the vaccine clones predominantly induced expression of pro-inflammatory cytokines in these mixed cultures, although one vaccine clone consistently induced production of IL-4. CD4 + T cells are the major cytokine-producing cells in these anti-vaccine lines. We could not detect upregulated antibody responses to the vaccine cells in most patients, although a temporary antibody response was observed in one patient. In conclusion, immunization with attenuated autoreactive T cells induces a complex cellular response specifically targeted at the vaccine cells, but no antibody responses. These data provide further insights into the mechanisms of T cell Vaccination and improve our understanding of the complex regulatory networks of autoreactive T cells.

Irina Kochetkova - One of the best experts on this subject based on the ideXlab platform.

  • Regulatory T-Cell Vaccination independent of auto-antigen
    Experimental and Molecular Medicine, 2014
    Co-Authors: David W Pascual, Xinghong Yang, Kathryn Holderness, Massimo Maddaloni, Irina Kochetkova
    Abstract:

    To date, efforts to treat autoimmune diseases have primarily focused on the disease symptoms rather than on the cause of the disease. In large part, this is attributed to not knowing the responsible auto-antigens (auto-Ags) for driving the self-reactivity coupled with the poor success of treating autoimmune diseases using oral tolerance methods. Nonetheless, if tolerogenic approaches or methods that stimulate regulatory T (Treg) cells can be devised, these could subdue autoimmune diseases. To forward such efforts, our approach with colonization factor antigen I (CFA/I) fimbriae is to establish bystander immunity to ultimately drive the development of auto-Ag-specific Treg cells. Using an attenuated Salmonella vaccine expressing CFA/I fimbriae, fimbriae-specific Treg cells were induced without compromising the vaccine's capacity to protect against travelers' diarrhea or salmonellosis. By adapting the vaccine's anti-inflammatory properties, it was found that it could also dampen experimental inflammatory diseases resembling multiple sclerosis (MS) and rheumatoid arthritis. Because of this bystander effect, disease-specific Treg cells are eventually induced to resolve disease. Interestingly, this same vaccine could elicit the required Treg cell subset for each disease. For MS-like disease, conventional CD25+ Treg cells are stimulated, but for arthritis CD39+ Treg cells are induced instead. This review article will examine the potential of treating autoimmune diseases without having previous knowledge of the auto-Ag using an innocuous antigen to stimulate Treg cells via the production of transforming growth factor-β and interleukin-10.

  • Regulatory T-Cell Vaccination independent of auto-antigen
    Experimental & Molecular Medicine, 2014
    Co-Authors: David W Pascual, Xinghong Yang, Kathryn Holderness, Massimo Maddaloni, Irina Kochetkova
    Abstract:

    A bacteria-based vaccine currently under development could protect against autoimmune diseases. In a review article, David W. Pascual from the University of Florida, USA, and his colleagues discuss how vaccines involving an attenuated strain of Salmonella—with an appendage called the colonization factor antigen I (CFA/I)—fimbriae help to induce components of the immune system called regulatory T cells. The vaccine protects against the causative agent of travelers' diarrhea, enterotoxigenic Escherichia coli. Further, by adapting the vaccine's properties, the same basic product in mice can dampen inflammatory diseases resembling multiple sclerosis and rheumatoid arthritis. The authors suggest that such a vaccine could help treat autoimmune diseases without having to know the specific antigens driving self-reactivity. As an added bonus, vaccine recipients might be protected against diarrheal diseases and salmonellosis. To date, efforts to treat autoimmune diseases have primarily focused on the disease symptoms rather than on the cause of the disease. In large part, this is attributed to not knowing the responsible auto-antigens (auto-Ags) for driving the self-reactivity coupled with the poor success of treating autoimmune diseases using oral tolerance methods. Nonetheless, if tolerogenic approaches or methods that stimulate regulatory T (T_reg) cells can be devised, these could subdue autoimmune diseases. To forward such efforts, our approach with colonization factor antigen I (CFA/I) fimbriae is to establish bystander immunity to ultimately drive the development of auto-Ag-specific T_reg cells. Using an attenuated Salmonella vaccine expressing CFA/I fimbriae, fimbriae-specific T_reg cells were induced without compromising the vaccine’s capacity to protect against travelers’ diarrhea or salmonellosis. By adapting the vaccine’s anti-inflammatory properties, it was found that it could also dampen experimental inflammatory diseases resembling multiple sclerosis (MS) and rheumatoid arthritis. Because of this bystander effect, disease-specific T_reg cells are eventually induced to resolve disease. Interestingly, this same vaccine could elicit the required T_reg cell subset for each disease. For MS-like disease, conventional CD25^+ T_reg cells are stimulated, but for arthritis CD39^+ T_reg cells are induced instead. This review article will examine the potential of treating autoimmune diseases without having previous knowledge of the auto-Ag using an innocuous antigen to stimulate T_reg cells via the production of transforming growth factor-β and interleukin-10.