Comparison of CNS homing pattern among murine TH cell lines responsive to myelin basic protein

Barbarese, Elisa; Soares, Holly; Yang, Sharlene; Clark, Robert B.

doi:10.1016/0165-5728(92)90184-m

Cited by 16 publications

(2 citation statements)

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“…Interestingly, our laboratory has previously published a study using a SJL adoptive transfer model of EAE and labeled T cell lines (20). Tracking the transferred T cells in that study revealed that day 4 after adoptive transfer appeared to be the key time point at which encephalitogenic T cells were restimulated in the CNS.…”

Section: Kinetics Of Tlr2 Tolerance Induction and Function Of L654 Inmentioning

confidence: 99%

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

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Section: Kinetics Of Tlr2 Tolerance Induction and Function Of L654 Inmentioning

confidence: 99%

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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“…However, all these techniques are hampered by cytotoxic side effects or marker dilution following multiple cell divisions. The latter problem is especially serious in studies of rapidly proliferating cells, such as activated encephalitogenic T cells [10][11][12][13] . An alternative approach is to identify transferred T cells using allogeneic markers.…”

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confidence: 99%

Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses

Flügel

Willem

Berkowicz

et al. 1999

Nat Med

143

141

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Encephalitogenic T cells can be isolated readily from naive or antigen-primed immune organs and propagated as clonal populations in vitro 1 . These T-cell lines have helped us to understand better epitope recognition, TCR gene use, cytokine patterns, and T-cell interactions with components of the CNS (ref.2), and have provided a basis for the design of new strategies to treat autoimmune diseases 3-6 .However, essential steps in the development of autoimmune disease have remained obscure. For example, it is well known that activated, autoaggressive T cells fail to attack the CNS immediately after transfer. The formation of an inflammatory infiltrate and associated tissue damage require a lag phase of at least 3 days. The events that occur during this period, in particular the distribution of the encephalitogenic T-cell population and the properties they assume, are unknown. The subsequent migration patterns of inflammatory cells within the target tissue, and their interaction modes with local brain cells, are also incompletely understood. Finally, most infiltrating T cells are known to undergo apoptotic death in the CNS lesion 7 , but whether or not some T cells survive and return to the periphery is controversial.Clarification of these questions requires methods that allow unequivocal identification of autoimmune T cells in experimental autoimmune encephalomyelitis (EAE) lesions and lymphoid tissues, and the re-isolation of transferred cells for functional characterization over time. These demands are satisfied by the genetic approach described here, which is based on introducing the green fluorescent protein (GFP) gene 8 into primary, brain-specific T lymphocytes. Our gene delivery protocol allows the routine generation of large panels of antigen-specific T cells that fully retain their (autoimmune) function and phenotype, and, at the same time, persistently express the fluorescent marker transgene. We show that GFP-engineered, myelin basic protein (MBP)-specific T cells mediate classic, acute EAE after transfer into syngeneic healthy animals. Furthermore, we show that these T cells can be tracked in vivo and re-isolated ex vivo for functional analysis. Finally, we demonstrate the integration of GFP-expressing cells in the immune repertoire of the Lewis rat and their persistence in vivo over several months. Retroviral transduction and selection of T lymphocytesWe achieved high-efficiency gene delivery into antigen-specific T lymphocytes by combining the gene-transfer step with primary in vitro selection for antigen specificity. We used a wellcharacterized retroviral vector (Fig. 1a) and a safety-modified packaging line as a transfer system. Primary T lymphocytes of preimmunized animals were cultivated together with packaging line cells, producing replication-deficient retrovirus. The Fig. 1 Retroviral gene vector and expression of GFP in CD4 + T lymphocytes.a, Retroviral vector construct pLGFPSN used to transduce CD4 + T lymphocytes. 5′LTR, long terminal repeat sequences (5′) driving expression of the transgene;...

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Internalization of microbubbles by tumor cellsin vivo andin vitro

Barbarese

D'Arrigo

et al. 1995

J Neuro-Oncol

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Lipid-coated microbubbles (LCM) administered intravenously (i.v.) to rats bearing brain tumor, specifically enhance tumor visualization by ultrasound [1]. In order to understand the basis for this observation, we have examined the interactions of LCM with glioblastoma (C6) and gliosarcoma (9L) tumor cells in vivo and in vitro. LCM and LCM labeled with the fluorescent lipophilic dye 3,3'-dioctadecyloxacarbocyanine perchlorate (diO) were administered to rats bearing brain tumor. LCM and diO-labeled LCM were found principally at the tumor site with no evidence of label in the surrounding normal brain tissue. Analysis of the tumor by confocal laser scanning microscopy revealed that labeled LCM were inside the tumor cells. Similar analysis of LCM interactions with C6 and 9L cells in culture showed that LCM first adsorb at the surface of the cells, and with time became localized inside the cells. Binding and internalization proceeded faster at 37 degrees C than at room temperature (RT). Staining of live cells with N-(3-((2,4-dinitrophenyl)amino)propyl)-N-(3-aminopropyl) methylamine dihydrochloride (DAMP), a dye that recognizes acidic compartments, showed that the majority of internalized LCM was associated with compartments containing DAMP. If the same uptake mechanism were operative in vivo, it would indicate that a portion of LCM bypasses the reticuloendothelial system and become endocytosed directly by tumor cells.

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Comparison of CNS homing pattern among murine TH cell lines responsive to myelin basic protein

Cited by 16 publications

References 16 publications

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses

Internalization of microbubbles by tumor cellsin vivo andin vitro

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