1 |
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CD40 in clinical inflammation: From multiple sclerosis to atherosclerosis
The interactions of CD40 and CD40L have been known for some time to critically regulate B-cell responses with respect to proliferation, isotype switching, antibody production, and memory formation. More recent findings demonstrated that CD40 can be expressed on several other antigen-presenting cell (APC) types such as macrophages, dendritic cells, and fibroblasts. This expression of CD40 regulates T-cell-APC interaction and is centrally involved in a wide array of inflammatory events. Here, currently available data are reviewed demonstrating that CD40-CD40L interactions are operational in two chronic inflammatory clinical conditions, namely, multiple sclerosis and atherosclerosis. The functional correlates of these interactions are discussed in the light of recent other findings, shedding light on the multiple effects of CD40-CD40L interactions.
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[Abstract]
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2 |
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Balancing the Th1/Th2 concept in multiple sclerosis
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3 |
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Role of Th1 and Th2 cells in autoimmune demyelinating disease
Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), whereas Th2 cells contribute to recovery from disease. A maj or determinant in the development of Th1 and Th2 cells is the type of antigen-presenting cell (APC) involved and its functional characteristics, e.g., the production of interleukin-12. Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE. The potential of cytokines, in particular interleukin-10, and glucocorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed.
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[PDF]
[Abstract]
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4 |
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Antigen-specific therapies in multiple sclerosis
Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategics are discussed that arc currently employed to selectively block the activation of T-cells reactive against myclin antigens.
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[Abstract]
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5 |
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CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis
article |
1996
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Author: |
Gerritse, K.
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Laman, J.D.
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Noelle, R.J.
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Aruffo, A.
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Ledbetter, J.A.
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Boersma, W.J.A.
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Claassen, E.
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Keywords: |
Health · Animals · Antibodies, Monoclonal · Antigens, CD40 · B-Lymphocytes · CD4-Positive T-Lymphocytes · CD40 Ligand · Encephalomyelitis, Autoimmune, Experimental · Female · Humans · Immunohistochemistry · Immunotherapy · Membrane Glycoproteins · Mice · Mice, Inbred Strains · Monocytes · Multiple Sclerosis · T-Lymphocytes, Helper-Inducer
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We investigated the role of CD40-CD40 ligand (CD40L) interactions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Activated helper T cells expressing CD40L (gp39) surface protein were found in MS patient brain sections, but not in brain tissue sections of normal controls or patients with other neurological diseases. CD40L-positive cells were co-localized with CD40-bearing cells in active lesions (perivascular infiltrates). Most of these CD40 bearing cells proved to be of the monocytic lineage (macrophages or microglial cells), and relatively few were B cells. To functionally evaluate CD40-CD40L interactions, EAE was elicited in mice by means of proteolipid-peptide immunization. Treatment with anti-CD40L monoclonal antibody completely prevented the development of disease. Furthermore, administration of anti-CD40L monoclonal antibody, even after disease onset, shortly before maximum disability score was reached led to dramatic disease reduction. The presence of helper T cells expressing CD40L in brain tissue of MS patients and EAE animals, together with the functional evidence provided by successful experimental prevention and therapy in an animal model, indicates that blockade of CD40-CD40L-mediated cellular interactions may be a method for interference in active MS.
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[PDF]
[Abstract]
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6 |
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Orally administered Lactobacillus strains differentially affect the direction and efficacy of the immune response
article |
1998
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Author: |
Maassen, C.B.M.
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Holten, J.C.A.M. van
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Balk, F.
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Heijne den Bak-Glashouwer, M.J.
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Leer, R.
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Laman, J.D.
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Boersma, W.J.A.
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Claassen, E.
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Keywords: |
Nutrition · lactobacillus vaccine · allergic encephalomyelitis · animal model · antibody blood level · conference paper · cytokine production · immune response · immunization · immunohistochemistry · lactobacillus · nonhuman · rat · Adjuvants, Immunologic · Administration, Oral · Animals · Antibody Formation · Cytokines · Encephalomyelitis, Autoimmune, Experimental · Female · gamma-Globulins · Intestine, Small · Lactobacillus · Mice · Mice, Inbred BALB C · Picrates · Probiotics · Cytokines · gamma-Globulins · Picrates · picric acid, 88-89-1
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In mice, strain dependent cytokine production profiles are induced after oral administration of Lactobacillus. Such a cytokine profile seems to determine the direction and efficacy of the humoral response. In SJL mice lactobacilli are able to enhance or inhibit the development of disease after induction of experimental autoimmune encephalomyelitis (EAE). Immuno- histochemical analysis of cytokine profiles showed that differential modulation is obtained dependent on the Lactobacillus strain applied. Serum antibody responses to i.p. immunisation with chicken gama globulin in BALB/c mice are also modulated by oral application of Lactobacillus. Lactobacilli are now being developed as safe live antigen carriers for application in vaccine technology, but also for the excretion of autoantigens in order to induce tolerance. The findings of this study imply that by proper strain selection the direction of the response can be influenced by the induction of a specific cytokine profile.
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[Abstract]
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7 |
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IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice
IL-10 and IL-4 were studied with respect to their capacity to inhibit experimental allergic encephalomyelitis (EAE) induced in SJL/J mice by immunization with the proteolipid protein peptide PLP139-151. Treatment with 2 μg IL-10/day from day 0 until day 12 delayed onset of disease and inhibited the severity of EAE. By contrast, a daily dose of 0.5 μg IL-4 was ineffective. Instead of acting in a synergistic fashion, IL-4 even abrogated the inhibitory effect of IL-10. The effects of IL-10 and IL-4 treatment were largely consistent with the (lack of) ability of these cytokines to down-regulate the inflammatory response in brain tissue. Although IL-4 was ineffective in the inhibition of EAE, lymph node cells from IL-4-treated mice displayed a strongly inhibited peptide-specific IFN-γ production. By contrast, IL-10, which was effective in inhibiting EAE, showed no significant inhibition of IFN-γ at this level. Neither cytokine treatment resulted in detectable levels of peptide-specific IL-4. Indirect evidence for the activity of T(h)2 cells in vivo came from the observation that IL-10 inhibited the primary PLP139-151-specific IgG2a and IgG3 response in favor of IgG1, whereas IL-4 inhibited the primary antibody response to the peptide, regardless of subclass. The combination of IL-4 and IL-10 did not affect the subclass composition. The observation that IL-10-treated mice remained sensitive to re-induction of EAE is not in support of an important role of T(h)2 cells in regulating disease activity in this model of actively induced EAE.
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[Abstract]
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8 |
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Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis
article |
1999
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Author: |
Howard, L.M.
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Miga, A.J.
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Vanderlugt, C.L.
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Dal Canto, M.C.
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Laman, J.D.
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Noelle, R.J.
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Miller, S.D.
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Keywords: |
Biology · Animals · Antibodies · CD4-Positive T-Lymphocytes · CD40 Ligand · Cell Differentiation · Cell Division · Central Nervous System · Disease Models, Animal · Encephalomyelitis, Autoimmune, Experimental · Female · Hypersensitivity, Delayed · Immunotherapy · Inflammation · Interferon Type II · Interleukins · Membrane Glycoproteins · Mice · Mice, Inbred Strains · Multiple Sclerosis · Myelin Proteolipid Protein · Myelin Sheath · Peptide Fragments · Th1 Cells
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Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS pathology. We asked whether blockade of the CD40-CD154 (CD40L) costimulatory pathway could suppress relapses in mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin (IL)-2, IL-4, IL- 5, and IL-10 were normal, antibody treatment severely inhibited interferon- γ production, myelin peptide-specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154 antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells, suggesting that CD40-CD154 interactions may be involved in directing the CNS migration of these cells and/or in their effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154-CD40 interactions is a promising immunotherapeutic strategy for treatment of ongoing T cell-mediated autoimmune diseases. Chemicals/CAS: Antibodies; CD40 Ligand, 147205-72-9; Interferon Type II, 82115-62-6; Interleukins; Membrane Glycoproteins; Myelin Proteolipid Protein; Peptide Fragments; proteolipid protein 139-151; proteolipid protein 178-191, 172228-98-7
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[PDF]
[Abstract]
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9 |
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IFN-beta modulates specific T cell responses in vitro but does not affect Experimental Autoimmune Encephalomyelitis in the SJL mouse
article |
1999
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Author: |
Luca, M.E.
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Visser, L.
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Lucas, C.J.
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Nagelkerken, L.
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Keywords: |
Biology · EAE · Interferon-β · Multiple sclerosis · Murine · T lymphocyte · Animals · Cells, Cultured · Dose-Response Relationship, Drug · Encephalomyelitis, Autoimmune, Experimental · Enzyme-Linked Immunosorbent Assay · Female · Interferon-beta · Interleukin-10 · Lymphocytes · Mice · Mice, Inbred Strains · Pertussis Toxin · Recombinant Proteins · Th2 Cells · Time Factors · Virulence Factors, Bordetella
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In this study, mouse recombinant IFN-β was shown to favor PLP139-151-specific Th2 responses in vitro, by inhibiting IFN-γ production and stimulating IL-4 and IL-10 production. IFN-β (5000 U/day) failed to prevent the development or severity of EAE induced with PLP139-151. Whereas efficacy of IL-10 was found in the B. pertussis assisted but not in the pertussigen-assisted EAE model, both models appeared insensitive to IFN-β. Also the combination of (suboptimal) IL-10 and IFN-β appeared ineffective in inhibiting disease. However, the PLP139-151-specific IL-10 production by T cells from these mice appeared significantly more sensitive to the stimulatory effect of IFN-β in vitro. It is concluded that despite its Th2 promoting effects, IFN-β is not effective in inhibiting EAE in this study. Copyright (C) 1999 Elsevier Science B.V. Chemicals/CAS: Interferon-beta, 77238-31-4; Interleukin-10, 130068-27-8; Pertussis Toxin, EC 2.4.2.31; Recombinant Proteins; Virulence Factors, Bordetella
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[Abstract]
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10 |
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Multiple sclerosis: An altered immune response or an altered stress response?
The pathogenesis of multiple sclerosis (MS), the major neurological disease of young adults in the Western world, is still poorly understood, and no effective therapy to block MS is available as yet. The clinical symptoms of MS result from inflammatory damage to the insulating myelin sheath of axons in the CNS and - at later stages - to axons themselves. A local autoimmune process involving activation of helper T cells against CNS protein components is likely to be crucial in this development. Especially at the first stages of MS, therapies aimed at the selective downregulation of MS-specific autoimmune responses may contribute to controlling the disease. Key to the success of such approaches is the identification of CNS proteins that are the target of local T cell responses. We recently identified the small heat-shock protein αB-crystallin as the single immunodominant myelin antigen in MS-affected myelin. This review discusses the functional and therapeutic implications of this finding along with other data on MS, and hypothesizes that an inappropriate stress response within the CNS itself is crucial as an initiating event in disease development.
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[Abstract]
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11 |
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Therapy with antibodies against CD40L (CD154) and CD44-variant isoforms reduces experimental autoimmune encephalomyelitis induced by a proteolipid protein peptide
article |
1998
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Author: |
Laman, J.D.
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Maassen, C.B.M.
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Schellekens, M.M.
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Visser, L.
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Kap, M.
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Jong, E. de
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Puijenbroek, M. van
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Stipdonk, M.J.B. van
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Meurs, M. van
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Schwärzler, C.
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Günthert, U.
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Keywords: |
Health · Accessory molecules · Blood-brain barrier · CD44 variant isoforms · Central nervous system (CNS) costimulation · Immunohistochemistry · Immunotherapy · Multiple sclerosis · Animals · Antibodies, Monoclonal · Antigens, CD40 · Antigens, CD44 · CD40 Ligand · Encephalomyelitis, Autoimmune, Experimental · Female · Immunization · Immunohistochemistry · Isoantigens · Membrane Glycoproteins · Mice · Myelin Proteolipid Protein · Peptide Fragments
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Interactions between mononuclear cells are required for the formation of inflammatory infiltrates in the CNS and the activation of cellular effector functions provoking demyelination in MS. Membrane-expressed costimulatory molecules are crucial to such interactions. We therefore investigated whether two costimulatory molecules, CD40L (CD154, expressed on activated CD4-possible T cells) and selected CD44-variant isoforms (expressed on activated CD4-positive T cells), are targets for immunotherapy in MS. The model of experimental autoimmune encephalomyelitis (EAE) induced in SJL-mice by immunization with a peptide derived from the proteolipid protein (PLP139-151) was optimized to address these questions. A previous observation that anti-CD40L (CD154) monoclonal antibodies can effectively prevent EAE in this model was confirmed and extended by demonstrating that CD40 is expressed by cells of the monocytic lineage infiltrating the spinal cord. In vivo treatment with antibody against the standard isoform of CD44 (CD44s or CD44H) did not affect disease burden. In contrast, combined treatment with antibodies against the isoforms CD44v6, v7 and v10, which are thought to be involved in inflammatory processes, reduced the disease burden considerably. In addition, CD44v10-expressing cells were detected in the spinal cord. These data support the idea that CD40-CD40L interactions form a target for immunotherapy of MS, and indicate that cells expressing CD44v6, v7 and/or v10-containing isoforms have such potential as well.
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[Abstract]
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12 |
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FcR interactions do not play a major role in inhibition of experimental autoimmune encephalomyelitis by anti-CD154 monoclonal antibodies
article |
2004
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Author: |
Nagelkerken, L.
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Haspels, I.
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Rijs, W. van
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Blauw, B.
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Ferrant, J.L.
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Hess, D.M.
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Garber, E.A.
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Taylor, F.R.
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Burkly, L.C.
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Keywords: |
CD40 ligand monoclonal antibody · allergic encephalomyelitis · allotransplantation · animal cell · animal experiment · animal model · cell infiltration · complement fixation · controlled study · fluorescence activated cell sorting · glycosylation · immunoreactivity · lymphocyte depletion · mouse · nonhuman · Th1 cell · Animals · Antibodies, Monoclonal · B-Lymphocytes · CD40 Ligand · Encephalomyelitis, Autoimmune, Experimental · Female · Glycosylation · Mice · Myelin Proteolipid Protein · Peptide Fragments · Receptors, Fc · T-Lymphocytes
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It has been demonstrated that anti-CD154 mAb treatment effectively inhibits the development of experimental autoimmune encephalomyelitis (EAE). However, although it appears to prevent the induction of Th1 cells and reactivation of encephalitogenic T cells within the CNS, little information is available regarding the involvement of alternative mechanisms, nor has the contribution of Fc effector mechanisms in this context been addressed. By contrast, efficacy of anti-CD154 mAbs in models of allotransplantation has been reported to involve long-term unresponsiveness, potentially via activation of T regulatory cells, and recently was reported to depend on Fc-dependent functions, such as activated T cell depletion through FcγR or complement. In this study we demonstrate that anti-CD154 mAb treatment inhibits EAE development in SJL mice without apparent long-term unresponsiveness or active suppression of disease. To address whether the mechanism of inhibition of EAE by anti-CD154 mAb depends on its Fc effector interactions, we compared an anti-CD154 mAb with its aglycosyl counterpart with severely impaired FcγR binding and reduced complement binding activity with regard to their ability to inhibit clinical signs of EAE and report that both forms of the Ab are similarly protective. This observation was largely confirmed by the extent of leukocyte infiltration of the CNS; however, mice treated with the aglycosyl form may display slightly more proteolipid protein 139-151-specific immune reactivity. It is concluded that FcR interactions do not play a major role in the protective effect of anti-CD154 mAb in the context of EAE, though they may contribute to the full abrogation of peripheral peptide-specific lymphocyte responses. Chemicals / CAS: Antibodies, Monoclonal; CD40 Ligand, 147205-72-9; Myelin Proteolipid Protein; Peptide Fragments; proteolipid protein 139-151; Receptors, Fc
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[Abstract]
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13 |
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Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)
article |
1998
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Author: |
Laman, J.D.
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Meurs, M. van
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Schellekens, M.M.
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Boer, M. de
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Melchers, B.
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Massacesi, L.
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Lassmann, H.
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Claassen, E.
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Hart, B.A. 't
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Keywords: |
Health · CD40 · CD80 · CD86 · Macrophages · Multiple sclerosis · Non-human primates · Acid Phosphatase · Animals · Antigens, CD · Antigens, CD40 · Antigens, CD80 · Antigens, CD86 · Brain · Brain Chemistry · Callithrix · Cytokines · Disease Models, Animal · Encephalomyelitis, Autoimmune, Experimental · Female · Histocompatibility Antigens Class II · HLA-DR Antigens · Interferon Type II · Interferon-alpha · Interleukin-1 · Interleukin-10 · Interleukin-12 · Interleukin-2 · Interleukin-4 · Macrophages · Male · Membrane Glycoproteins · Multiple Sclerosis · Tumor Necrosis Factor-alpha
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Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of marmoset monkeys (Callithrix jacchus) with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions may result from local CD40-CD40L interactions. CD40 ligand (CD40L) and B7-2 (CD86) were also expressed, but to a lower extent, while B7-1 (CD80) expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual lesions during active disease (IFN-α, IFN-γ, TNF-α, IL-1 α, IL-1β, IL-2, IL-4, IL-10 and IL-12). This suggests that relative levels rather than sequential expression of Th1- and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention.
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[Abstract]
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14 |
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Tolerance controls encephalitogenicity of αB-crystallin in the Lewis rat
article |
2000
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Author: |
Stipdonk, M.J.B. van
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Willems, A.A.
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Plomp, A.C.
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Noort, J.M. van
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Boog, C.J.P.
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Keywords: |
Health · Tolerance · Autoantigen · Crystallin · Myelin · Myelin associated glycoprotein · Allergic encephalomyelitis · Animal cell · Animal experiment · Autoimmune disease · Central nervous system · Controlled study · Immunization · Lymphocyte proliferation · Multiple sclerosis · Nonhuman · Rat strain · T lymphocyte · Animals · Autoantigens · Cattle · Crystallins · Dose-Response Relationship, Immunologic · Encephalomyelitis, Autoimmune, Experimental · Hypersensitivity, Delayed · Immune Tolerance · Immunity, Cellular · Immunodominant Epitopes · Lymphoid Tissue · Male · Mice · Organ Specificity · Peptide Fragments · Phosphorylation · Rats · Rats, Inbred Lew · Reverse Transcriptase Polymerase Chain Reaction · RNA, Messenger · Species Specificity · T-Lymphocytes
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The myelin-associated protein, αB-crystallin, is considered a candidate autoantigen in multiple sclerosis (MS). In the present study, we examined the potential of αB-crystallin to induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Attempts to induce EAE with either bovine, rat or murine αB-crystallin or αB-crystallin peptides consistently failed. Immunization with either autologous rat or murine αB-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine αB-crystallin or a synthetic peptide representing the cryptic epitope 49-64 did trigger T cell responses but these failed to crossreact with autologous rat αB-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of αB-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of αB-crystallin is associated with a state of nonresponsiveness to autologous αB-crystallin that effectively controls the development of EAE in response to this myelin antigen. Copyright (C) 2000 Elsevier Science B.V. Chemicals/CAS: Autoantigens; Crystallins; Immunodominant Epitopes; Peptide Fragments; RNA, Messenger
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[Abstract]
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15 |
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T- and B-cell nonresponsiveness to self-αB-crystallin in SJL mice prevents the induction of experimental allergic encephalomyelitis
The myelin-associated stress protein αB-crystallin triggers strong proliferative responses and IFN-γ production by human T cells and it is considered a candidate autoantigen in multiple sclerosis. In this study we examined the capacity of αB-crystallin or peptides derived thereof to induce experimental autoimmune encephalomyelitis (EAE) in SJL mice. Despite extensive efforts to induce EAE using active immunization with whole αB-crystallin, using adoptive transfer of lymphocytes or using peptide immunizations, no clinical or histological signs of EAE could be induced. SJL mice were unable to mount proliferative T-cell responses in vitro or delayed-type hypersensitivity responses in vivo to self-αB-crystallin. Also, immunization with self-αB-crystallin did not lead to any antibody response in SJL mice while bovine αB-crystallin triggered clear antibody responses within 1 week. Immunizations with αB-crystallin-derived peptides led to the activation of IL-4-producing Th2 cells and only a few IFN-γ-producing Th1 cells. Peptide-specific T cells showed no cross-reactivity against whole αB-crystallin. The inability of SJL mice to mount proinflammatory T-cell responses against self-αB-crystallin readily explains the lack of EAE induction by immunization with whole protein or peptides derived from it. T- and B-cell nonresponsiveness is associated with constitutive expression of full-length αB-crystallin in both primary and secondary lymphoid organs in SJL mice, which is seen in other mammals as well, but not in humans. (C) 2000 Academic Press. Chemicals/CAS: Crystallins; H-2 Antigens; Interferon Type II, 82115-62-6; Interleukin-4, 207137-56-2; Nerve Tissue Proteins
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[Abstract]
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16 |
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1H-NMR spectroscopy combined with pattern recognition analysis reveals characteristic chemical patterns in urines of MS patients and non-human primates with MS-like disease
article |
2003
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Author: |
Hart, B.A. 't
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Vogels, J.T.W.E.
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Spijksma, G.
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Brok, H.P.M.
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Polman, C.
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Greef, J. van der
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Keywords: |
Biology · Analytical research · Inflammatory demyelination · MS disease markers · NMR spectroscopy · Pattern recognition · Urine · myelin protein · organic compound · glycoprotein · tritium · animal model · article · autoimmune disease · chemical composition · clinical article · controlled study · disease course · encephalomyelitis · female · human · male · marmoset · molecular recognition · multiple sclerosis · multivariate analysis · nonhuman · primate · priority journal · proton nuclear magnetic resonance · urinalysis · validation process · allergic encephalomyelitis · animal · automated pattern recognition · chemistry · comparative study · disease model · immunization · immunology · methodology · nuclear magnetic resonance spectroscopy · species difference · time · urine · Animals · Callithrix · Disease Models, Animal · Encephalomyelitis, Autoimmune, Experimental · Female · Glycoproteins · Humans · Immunization · Magnetic Resonance Spectroscopy · Male · Multiple Sclerosis · Multivariate Analysis · Myelin Proteins · Pattern Recognition, Automated · Species Specificity · Time Factors · Tritium · Urine
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Proton nuclear magnetic resonance (1H-NMR) spectroscopy in combination with pattern recognition techniques were used to investigate the composition of organic compounds in urines from patients with multiple sclerosis (MS), patients with other neurological diseases (OND) and healthy controls (H). Using a valid animal model of MS, namely the common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE), the relation of disease progression and alteration of the urine composition was investigated. Urine samples were collected during different stages of EAE, either induced with whole human myelin or with the myelin protein MOG in complete adjuvant. The urine samples were analysed with 1H-NMR spectroscopy allowing simultaneous detection of an array of compounds. Spectral differences between urines from EAE-affected and healthy monkeys were assessed with multivariate analysis. Evidence is provided that development of EAE is associated with changes in the chemical composition of the urine, in particular of compounds with NMR peaks in the region of the spectrum between 0.5 and 3.50 ppm. In addition, we found preliminary evidence for differences between urines from MS, OND and H groups. © 2003 Elsevier Science B.V. All rights reserved. Chemicals/CAS: tritium, 10028-17-8; Glycoproteins; Myelin Proteins; Tritium, 10028-17-8
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[Abstract]
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17 |
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Non-invasive measurement of brain damage in a primate model of multiple sclerosis
article |
2004
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Author: |
T Hart, B.A.
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Vogels, J.
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Bauer, J.
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Brok, H.P.M.
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Blezer, E.
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Keywords: |
Biology Health · Analytical research · myelin · allergic encephalomyelitis · brain injury · chemometric analysis · demyelination · diagnostic imaging · human · immunopathology · marmoset · multiple sclerosis · neurologic disease · neuropathology · non invasive measurement · nonhuman · nuclear magnetic resonance imaging · nuclear magnetic resonance spectroscopy · pattern recognition · positron emission tomography · proton nuclear magnetic resonance · review · urinalysis · white matter · X ray analysis · Animals · Animals, Outbred Strains · Antigens, CD · Biological Markers · Brain · Callithrix · CD4-Positive T-Lymphocytes · Chronic Disease · Demyelinating Diseases · Disease Models, Animal · Encephalomyelitis, Autoimmune, Experimental · Genes, MHC Class II · Humans · Magnetic Resonance Imaging · Magnetic Resonance Spectroscopy · Mice · Multiple Sclerosis · Myelin Basic Proteins · Myelin-Associated Glycoprotein · T-Lymphocytes, Cytotoxic · Th2 Cells · Animalia · Callithrix · Callithrix jacchus · marmosets · Primates · Rodentia
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Early recognition of whether a product has potential as a new therapy for treating multiple sclerosis (MS) relies upon the quality of the animal models used in the preclinical trials. The promising effects of new treatments in rodent models of experimental autoimmune encephalomyelitis (EAE) have rarely been reproduced in patients suffering from MS. EAE in outbred marmoset monkeys, Callithrix jacchus, is a valid new model, and might provide an experimental link between EAE in rodent models and human MS. Using magnetic resonance imaging techniques similar to those used in patients suffering from MS pathological abnormalities in the brain, white matter of the animal can be visualized and quantified. Moreover, NMR spectroscopy, in combination with pattern recognition, offers an advanced uroscopic technique for the identification of biomarkers of inflammatory demyelination.
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[Abstract]
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18 |
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Soluble mannosylated myelin peptide inhibits the encephalitogenicity of autoreactive T cells during experimental autoimmune encephalomyelitis
article |
2007
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Author: |
Kel, J.
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Oldenampsen, J.
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Luca, M.
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Drijfhout, J.W.
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Koning, F.
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Nagelkerken, L.
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Keywords: |
Biology · Biomedical Research · gamma interferon · interleukin 23 · major histocompatibility antigen class 2 · myelin · proteolipid · autoantigen · epitope · lymphocyte antigen receptor · mannose · peptide fragment · proteolipid protein · proteolipid protein 139 151 · proteolipid protein 139-151 · allergic encephalomyelitis · animal cell · animal experiment · animal model · animal tissue · article · controlled study · drug mechanism · female · histopathology · immunization · immunomodulation · immunoreactivity · incidence · macrophage · mouse · nonhuman · priority journal · solubility · spinal cord · T lymphocyte · animal · chemistry · drug effect · immunology · inflammation · lymphocyte activation · pathology · Animals · Autoantigens · Encephalomyelitis, Autoimmune, Experimental · Female · Immunodominant Epitopes · Inflammation · Lymphocyte Activation · Mannose · Mice · Myelin Proteolipid Protein · Peptide Fragments · Receptors, Antigen, T-Cell · Spinal Cord · T-Lymphocytes
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We have previously shown that immunization with a mannosylated myelin peptide in complete adjuvant induces tolerance instead of disease in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis. In this report we demonstrate that treatment with a soluble mannosylated epitope of proteolipid protein (M-PLP139-151) significantly inhibits disease mediated by autoreactive myelin-specific T cells during EAE. Treatment with M-PLP139-151, applied in different EAE models, significantly reduced the incidence of disease and the severity of clinical symptoms. Delayed-type hypersensitivity responses were abolished after peptide treatment, emphasizing the impact on peripheral T-cell reactivity. Histological analysis of spinal cord tissue from mice treated with M-PLP 139-151 revealed the presence of only few macrophages and T cells. Moreover, little expression of interferon-γ, interleukin-23, or major histocompatibility complex class II antigen was detected. Immune modulation by M-PLP139-151 was primarily antigen-specific because an irrelevant mannosylated peptide showed no significant effect on delayed-type hypersensitivity responses or on the course of EAE. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo. Copyright © American Society for Investigative Pathology.
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[Abstract]
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Induction of EAE by T cells specific for alpha B-crystallin depends on prior viral infection in the CNS
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2007
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Author: |
Verbeek, R.
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Dongen, H. van
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Wawrousek, E.F.
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Amor, S.
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Noort, J.M. van
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Keywords: |
Biology · Biomedical Research · alpha crystallin · myelin · allergic encephalomyelitis · animal cell · animal experiment · animal model · antigen expression · article · brain infection · cell specificity · controlled study · encephalitis · immune response · immunological tolerance · lymphocyte transfer · mouse · multiple sclerosis · nonhuman · pathogenicity · priority journal · recipient · Semliki Forest alphavirus · T lymphocyte · T lymphocyte activation · virus infection · virus strain · virus virulence · Adoptive Transfer · alpha-Crystallin B Chain · Alphavirus Infections · Animals · Cells, Cultured · Central Nervous System Viral Diseases · Encephalomyelitis, Autoimmune, Experimental · Immune Tolerance · Inflammation Mediators · Lymphocyte Activation · Mice · Mice, Biozzi · Mice, Inbred C57BL · Mice, Knockout · Semliki forest virus · Spinal Cord · T-Lymphocytes · Time Factors
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While myelin-reactive T cells are widely believed to play a pathogenic role in multiple sclerosis (MS), no substantial differences appear to exist in T-cell responses to myelin antigens between MS patients and healthy subjects. As an example, indistinguishable peripheral T-cell responses and serum antibody levels have been found in MS patients and healthy controls to alpha B-crystallin, a dominant antigen in MS-affected brain myelin. This suggests that additional factors are relevant in allowing myelin-reactive T cells to become pathogenic. In this study, we examined whether the inflammatory state of the CNS is relevant to the pathogenicity of alpha B-crystallin-specific T cells in mice. In normal mice, T-cell responses against alpha B-crystallin are limited by robust immunological tolerance. Reactive T cells were therefore generated in alpha B-crystallin-deficient mice, and these T cells were transferred into C57BL/6 recipients. While such a transfer in itself never induced any clinical signs of experimental autoimmune encephalomyelitis (EAE) in healthy recipient mice, acute EAE could be induced in animals that had been infected 7 days before with the avirulent A7(74) strain of Semliki Forest virus (SFV). SFV infection alone did not induce clinical disease, nor did it alter the expression levels of the target antigen. Our findings indicate that at least in mice, alpha B-crystallin-specific T cells can trigger EAE but only when prior viral infection has induced an inflammatory state in the CNS that helps recruit and activate T cells. © 2007 Oxford University Press.
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[Abstract]
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20 |
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Mannosylated self-peptide inhibits the development of experimental autoimmune encephalomyelitis via expansion of nonencephalitogenic T cells
Tolerance to experimental autoimmune encephalomyelitis (EAE) in SJL mice can be induced by immunization with a mannosylated form of the proteolipid protein (M-PLP139-151), despite the presence of CFA. The state of tolerance is characterized by poor delayed-type hypersensitivity responses and the absence of clinical EAE symptoms. In vivo monitoring of CFSE-labeled PLP139-151-specific TCR-transgenic (5B6) T cells revealed that immunization with M-PLP139-151 increases the clonal expansion of 5B6 T cells that do not develop full effector functions. Moreover, nonfunctional T cells obtained from M-PLP139-151-immunized mice showed poor blastogenesis and were unable to transfer EAE to naïve recipients. Nevertheless, the in vitro production of cytokines and chemokines associated with EAE was unaffected. Importantly, tolerance induced by M-PLP 139-151 was abrogated by the administration of pertussis toxin, resulting in EAE development. Our results suggest that M-PLP139-151 inhibits EAE development by affecting the differentiation of T cells into encephalitogenic effector cells. © Society for Leukocyte Biology.
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[Abstract]
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