8 results
Search Results
2. Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity.
- Author
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Waisman, Ari and Johann, Lisa
- Subjects
T cells ,CENTRAL nervous system ,ANTIGENS ,AUTOIMMUNITY ,MULTIPLE sclerosis ,OLIGODENDROGLIA - Abstract
Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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3. Oral Tolerance Induction in Experimental Autoimmune Encephalomyelitis with Candida utilis Expressing the Immunogenic MOG35-55 Peptide.
- Author
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Buerth, Christoph, Mausberg, Anne K., Heininger, Maximilian K., Hartung, Hans-Peter, Kieseier, Bernd C., and Ernst, Joachim F.
- Subjects
ENCEPHALOMYELITIS ,MULTIPLE sclerosis ,PEPTIDES ,AUTOIMMUNITY ,SPINAL cord ,DEMYELINATION - Abstract
Multiple sclerosis (MS) is an autoimmune disease that attacks myelinated axons in the central nervous system. Induction of oral tolerance is a potent mechanism to prevent autoimmunity. The food yeast Candida utilis was used to test the therapeutic potential of oral tolerance induction in an animal model of human multiple sclerosis (MS). We constructed a C. utilis strain, which displays a fusion peptide composed of the encephalitogenic MOG
35-55 peptide and the C. utilis Gas1 cell wall protein on its surface.By immunizing mice with MOG35-55 peptide experimental autoimmune encephalomyelitis (EAE) was induced in a mouse model. Feeding of mice with C. utilis that expresses MOG35-55 peptide on its surface was started seven days prior to immunization and was continued for ten days. Control animals were treated with wild-type fungus or left untreated. Untreated mice developed first clinical symptoms ten days post immunization (p. i.) with an ascending paralysis reaching maximal clinical disability at day 18 to 20 p. i.. Treatment with the wild-type strain demonstrated comparable clinical symptoms. In contrast, oral gavage of MOG35-55 -presenting fungus ameliorated the development of EAE. In addition, incidence as well as maximal clinical disease severity were significantly reduced. Interestingly, reduction of disease severity also occurred in animals treated with heat-inactivated C. utilis cells indicating that tolerance induction was independent of fungal viability. Better disease outcome correlated with reduced demyelination and cellular inflammation in the spinal cord, lower T cell proliferation against rechallenge with MOG35-55 and more regulatory T cells in the lymph nodes. Our data demonstrate successful that using the food approved fungus C. utilis presenting the immunogenic MOG35-55 peptide on its surface induced an oral tolerance against this epitope in EAE. Further studies will reveal the nature and extent of an anti-inflammatory environment established by the treatment that prevents the development of an autoimmune disorder affecting the CNS. [ABSTRACT FROM AUTHOR]- Published
- 2016
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4. Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE.
- Author
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Esen, Nilufer, Katyshev, Vladimir, Serkin, Zakhar, Katysheva, Svetlana, and Dore-Duffy, Paula
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IMMUNOLOGICAL aspects of encephalomyelitis ,AUTOIMMUNITY ,MYELIN oligodendrocyte glycoprotein ,ANGIOPLASTY ,BIOLOGICAL adaptation ,T cell receptors ,CELL metabolism ,PROTEIN metabolism ,PHYSIOLOGICAL adaptation ,ANIMAL experimentation ,HYPOXEMIA ,ANTIGENS ,BIOLOGICAL models ,CENTRAL nervous system ,DEMYELINATION ,IMMUNITY ,INTERFERONS ,INTERLEUKINS ,MICE ,OXYGEN ,PEPTIDES ,SOLUTION (Chemistry) ,SPINAL cord ,T cells ,TIME ,MEMBRANE glycoproteins - Abstract
Background: In the brain, chronic inflammatory activity may lead to compromised delivery of oxygen and glucose suggesting that therapeutic approaches aimed at restoring metabolic balance may be useful. In vivo exposure to chronic mild normobaric hypoxia (10 % oxygen) leads to a number of endogenous adaptations that includes vascular remodeling (angioplasticity). Angioplasticity promotes tissue survival. We have previously shown that induction of adaptive angioplasticity modulates the disease pattern in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). In the present study, we define mechanisms by which adaptation to low oxygen functionally ameliorates the signs and symptoms of EAE and for the first time show that tissue hypoxia may fundamentally alter neurodegenerative disease.Methods: C57BL/6 mice were immunized with MOG, and some of them were kept in the hypoxia chambers (day 0) and exposed to 10 % oxygen for 3 weeks, while the others were kept at normoxic environment. Sham-immunized controls were included in both hypoxic and normoxic groups. Animals were sacrificed at pre-clinical and peak disease periods for tissue collection and analysis.Results: Exposure to mild hypoxia decreased histological evidence of inflammation. Decreased numbers of cluster of differentiation (CD)4+ T cells were found in the hypoxic spinal cords associated with a delayed Th17-specific cytokine response. Hypoxia-induced changes did not alter the sensitization of peripheral T cells to the MOG peptide. Exposure to mild hypoxia induced significant increases in anti-inflammatory IL-10 levels and an increase in the number of spinal cord CD25+FoxP3+ T-regulatory cells.Conclusions: Acclimatization to mild hypoxia incites a number of endogenous adaptations that induces an anti-inflammatory milieu. Further understanding of these mechanisms system may pinpoint possible new therapeutic targets to treat neurodegenerative disease. [ABSTRACT FROM AUTHOR]- Published
- 2016
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5. SJL Mice Infected with Acanthamoeba castellanii Develop Central Nervous System Autoimmunity through the Generation of Cross-Reactive T Cells for Myelin Antigens.
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Massilamany, Chandirasegaran, Marciano-Cabral, Francine, Rocha-Azevedo, Bruno da, Jamerson, Melissa, Gangaplara, Arunakumar, Steffen, David, Zabad, Rana, Illes, Zsolt, Sobel, Raymond A., and Reddy, Jay
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ACANTHAMOEBA castellanii ,LABORATORY mice ,CENTRAL nervous system ,AUTOIMMUNITY ,T cells ,MYELIN ,ANTIGENS - Abstract
We recently reported that Acanthamoeba castellanii (ACA), an opportunistic pathogen of the central nervous system (CNS) possesses mimicry epitopes for proteolipid protein (PLP) 139–151 and myelin basic protein 89–101, and that the epitopes induce experimental autoimmune encephalomyelitis (EAE) in SJL mice reminiscent of the diseases induced with their corresponding cognate peptides. We now demonstrate that mice infected with ACA also show the generation of cross-reactive T cells, predominantly for PLP 139–151, as evaluated by T cell proliferation and IA
s /dextramer staining. We verified that PLP 139–151-sensitized lymphocytes generated in infected mice contained a high proportion of T helper 1 cytokine-producing cells, and they can transfer disease to naïve animals. Likewise, the animals first primed with suboptimal dose of PLP 139–151 and later infected with ACA, developed EAE, suggesting that ACA infection can trigger CNS autoimmunity in the presence of preexisting repertoire of autoreactive T cells. Taken together, the data provide novel insights into the pathogenesis of Acanthamoeba infections, and the potential role of infectious agents with mimicry epitopes to self-antigens in the pathogenesis of CNS diseases such as multiple sclerosis. [ABSTRACT FROM AUTHOR]- Published
- 2014
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6. Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma.
- Author
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Choi, Bryan D., Chien-Tsun Kuan, Mingqing Cai, Archer, Gary E., Mitchell, Duane A., Gedeon, Patrick C., Sanchez-Perez, Luis, Pastan, Ira, Bigner, Darell D., and Sampson, John H.
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BISPECIFIC antibodies ,GLIOMA treatment ,EPIDERMAL growth factor ,T cells ,ANTIGENS ,IMMUNOTHERAPY - Abstract
Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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7. P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation.
- Author
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Kooij, Gijs, Backer, Ronald, Koning, Jasper J., Reijerkerk, Arie, van Horssen, Jack, van der Pol, Susanne M. A., Drexhage, Joost, Schinkel, Alfred, Dijkstra, Christine D., den Haan, Joke M. M., Geijtenbeek, Teunis B. H., and de Vries, Helga E.
- Subjects
P-glycoprotein ,IMMUNOMODULATORS ,MULTIPLE sclerosis ,DEMYELINATION ,CENTRAL nervous system ,T cells ,MYELINATION ,ANTIGENS ,DENDRITIC cells - Abstract
Background: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which autoreactive myelin-specific T cells cause extensive tissue damage, resulting in neurological deficits. In the disease process, T cells are primed in the periphery by antigen presenting dendritic cells (DCs). DCs are considered to be crucial regulators of specific immune responses and molecules or proteins that regulate DC function are therefore under extensive investigation. We here investigated the potential immunomodulatory capacity of the ATP binding cassette transporter P-glycoprotein (Pgp). P-gp generally drives cellular efflux of a variety of compounds and is thought to be involved in excretion of inflammatory agents from immune cells, like DCs. So far, the immunomodulatory role of these ABC transporters is unknown. Methods and Findings: Here we demonstrate that P-gp acts as a key modulator of adaptive immunity during an in vivo model for neuroinflammation. The function of the DC is severely impaired in P-gp knockout mice (Mdr1a/1b-/-), since both DC maturation and T cell stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b -/- mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF-α and IFN-γ. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines. Conclusions: Our data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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8. Immune Regulatory Neural Stem/Precursor Cells Protect from Central Nervous System Autoimmunity by Restraining Dendritic Cell Function.
- Author
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Pluchino, Stefano, Zanotti, Lucia, Brambilla, Elena, Rovere-Querini, Patrizia, Capobianco, Annalisa, Alfaro-Cervello, Clara, Salani, Giuliana, Cossetti, Chiara, Borsellino, Giovanna, Battistini, Luca, Ponzoni, Maurilio, Doglioni, Claudio, Garcia-Verdugo, Jose Manuel, Comi, Giancarlo, Manfredi, Angelo A., and Martino, Gianvito
- Subjects
NEURAL stem cells ,CENTRAL nervous system ,AUTOIMMUNITY ,DENDRITIC cells ,ENCEPHALOMYELITIS ,ANTIGENS ,T cells - Abstract
Background: The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinicopathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. Methodology/Principal Findings: To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal upregulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigenspecific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation. Conclusion/Significance: The study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
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