Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model

2004 ◽  
Vol 10 (2) ◽  
pp. 158-164 ◽  
Author(s):  
Xiang Ni ◽  
Ellen B Geller ◽  
Michael J Eppihimer ◽  
Toby K Eisenstein ◽  
Martin W Adler ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Preliminary Evidence ◽  
Leukocyte Rolling ◽  
Inhibitory Effects ◽  
Autoimmune Encephalomyelitis ◽  
Cranial Window ◽  
The Central Nervous System ◽  
Demyelinating Disorders ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (C NS). Leukocyte/endothelial interactions are important steps in the progression of the disease and substances that interfere with these activities have been evaluated as potential therapeutic agents. C annabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpo se of this investigation was to determine how cannabinoid recepto r agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalo myelitis (EAE) model using six to eight week old C 57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, C B1 and C B2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactio ns were evaluated via a cranial window implanted two days before. The results demonstrated that EAE increases leukocyte rolling and firm adhesion in the brain, and that this increased leukocyte/endothelial interactio n can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the C B1 recepto r (SR 141716A) and the C B2 receptor (SR144528) in this study demonstrated that the cannabinoid’s inhibitory effects on leukocyte/endothelial interactions can be mediated by activating C B2 receptor.

scholarly journals Thrombin Cleavage of Osteopontin Modulates Its Activities in Human CellsIn Vitroand Mouse Experimental Autoimmune EncephalomyelitisIn Vivo

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Elena Boggio ◽  
Chiara Dianzani ◽  
Casimiro Luca Gigliotti ◽  
Maria Felicia Soluri ◽  
Nausicaa Clemente ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Published Data ◽  
Autoimmune Encephalomyelitis ◽  
Thrombin Cleavage ◽  
The Central Nervous System ◽  
Potent Drug ◽  
Fine Tune ◽  
Experimental Autoimmune

Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction withα4β1integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated,in vitro,their effect on human cells andin vivoin EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects bothin vitroandin vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases.

scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals Anti-Axl antibody treatment reduces the severity of experimental autoimmune encephalomyelitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Juwen C. DuBois ◽  
Alex K. Ray ◽  
Peter Davies ◽  
Bridget Shafit-Zagardo
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Immune Cell ◽  
Autoimmune Encephalomyelitis ◽  
Antibody Treatment ◽  
The Central Nervous System ◽  
Inflammatory Macrophages ◽  
Experimental Autoimmune

Abstract Background Multiple sclerosis is an immune-mediated disease of the central nervous system (CNS) characterized by inflammation, oligodendrocytes loss, demyelination, and damaged axons. Tyro3, Axl, and MerTK belong to a family of receptor tyrosine kinases that regulate innate immune responses and CNS homeostasis. During experimental autoimmune encephalomyelitis (EAE), the mRNA expression of MerTK, Gas6, and Axl significantly increase, whereas Tyro3 and ProS1 remain unchanged. We have shown that Gas6 is neuroprotective during EAE, and since Gas6 activation of Axl may be necessary for conferring neuroprotection, we sought to determine whether α-Axl or α-MerTK antibodies, shown by others to activate their respective receptors in vivo, could effectively reduce inflammation and neurodegeneration. Methods Mice received either α-Axl, α-MerTK, IgG isotype control, or PBS before the onset of EAE symptoms. EAE clinical course, axonal damage, demyelination, cytokine production, and immune cell activation in the CNS were used to determine the severity of EAE. Results α-Axl antibody treatment significantly decreased the EAE clinical indices of female mice during chronic EAE and of male mice during both acute and chronic phases. The number of days mice were severely paralyzed also significantly decreased with α-Axl treatment. Inflammatory macrophages/microglia and the extent of demyelination significantly decreased in the spinal cords of α-Axl-treated mice during chronic EAE, with no differences in the production of pro-inflammatory cytokines. α-MerTK antibody did not influence EAE induction or progression. Conclusion Our data suggests that the beneficial effect of Gas6/Axl signaling observed in mice administered with Gas6 can be partially preserved by administering an activating α-Axl antibody, but not α-MerTK.

scholarly journals The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

scholarly journals Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation

2022 ◽  
Vol 12 ◽  
Author(s):  
Mathias Linnerbauer ◽  
Lena Lößlein ◽  
Daniel Farrenkopf ◽  
Oliver Vandrey ◽  
Thanos Tsaktanis ◽  
...  
Keyword(s):  
Late Phase ◽  
Recovery Phase ◽  
Preclinical Model ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Signaling ◽  
Cns Inflammation ◽  
Human Astrocytes ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.

scholarly journals Prevention of EAE by PEGylated Antigenic Peptides

2020 ◽  
Author(s):  
Jennifer Pfeil ◽  
Mario Simonetti ◽  
Uta Lauer ◽  
Bianca von Thülen ◽  
Pawel Durek ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immunosuppressive Drugs ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Overt Disease ◽  
Specific Tolerance ◽  
Experimental Autoimmune

AbstractThe treatment of autoimmune disorders such as multiple sclerosis (MS) so far relies largely on the use of non-specific immunosuppressive drugs, which are not able to cure the disease. Presently, approaches to induce antigen-specific tolerance e.g. by peptide-based tolerogenic “inverse” vaccines regain interest. We previously have shown that coupling of peptides to carriers can enhance their capacity to induce regulatory T cells in vivo. We here investigated in an experimental autoimmune encephalomyelitis (EAE) model for chronic MS (MOG C57BL/6) whether the tolerogenic potential of immunodominant myelin T cell epitopes can be improved by conjugation to the synthetic carrier polyethylene glycol (PEG). Indeed, preventive administration of the PEGylated antigenic peptide could almost completely protect mice from EAE development, which was accompanied by reduced immune cell infiltration in the central nervous system (CNS). Depletion of Tregs abrogated the protective effect indicating that Tregs play a crucial role in induction of antigen-specific tolerance in EAE. Treatment during the acute phase was safe and did not induce immune activation. However, treatment at the peak of disease was not affecting the disease course, suggesting that either induction of Tregs is not occurring in the highly inflamed situation, or that the immune system is refractory to regulation in this condition. Thus, PEGylation of antigenic peptides is an effective and feasible strategy to improve tolerogenic (Treg-inducing) peptide-based vaccines, but application in overt disease might require modifications or combination therapies that simultaneously suppress effector mechanisms.

scholarly journals CD8+ T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Neda Feizi ◽  
Chiara Focaccetti ◽  
Ilenia Pacella ◽  
Gloria Tucci ◽  
Alessandra Rossi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Severity ◽  
Effector Memory ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

AbstractThe autoimmune immunopathology occurring in multiple sclerosis (MS) is sustained by myelin-specific and -nonspecific CD8+ T cells. We have previously shown that, in MS, activated T cells undergoing apoptosis induce a CD8+ T cell response directed against antigens that are unveiled during the apoptotic process, namely caspase-cleaved structural proteins such as non-muscle myosin and vimentin. Here, we have explored in vivo the development and the function of the immune responses to cryptic apoptosis-associated epitopes (AEs) in a well-established mouse model of MS, experimental autoimmune encephalomyelitis (EAE), through a combination of immunization approaches, multiparametric flow cytometry, and functional assays. First, we confirmed that this model recapitulated the main findings observed in MS patients, namely that apoptotic T cells and effector/memory AE-specific CD8+ T cells accumulate in the central nervous system of mice with EAE, positively correlating with disease severity. Interestingly, we found that AE-specific CD8+ T cells were present also in the lymphoid organs of unprimed mice, proliferated under peptide stimulation in vitro, but failed to respond to peptide immunization in vivo, suggesting a physiological control of this response. However, when mice were immunized with AEs along with EAE induction, AE-specific CD8+ T cells with an effector/memory phenotype accumulated in the central nervous system, and the disease severity was exacerbated. In conclusion, we demonstrate that AE-specific autoimmunity may contribute to immunopathology in neuroinflammation.

scholarly journals Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Letscher ◽  
Viviane A. Agbogan ◽  
Sarantis Korniotis ◽  
Pauline Gastineau ◽  
Emmanuel Tejerina ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Toll Like Receptor ◽  
Hematopoietic Progenitors ◽  
Autoimmune Encephalomyelitis ◽  
Hematopoietic Precursor ◽  
Therapeutic Properties ◽  
Experimental Autoimmune

AbstractEarly innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.

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