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A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC.

ABSTRACT: Cytokine-NAg fusion proteins represent an emerging platform for specific targeting of self-antigen to particular APC subsets as a means to achieve antigen-specific immunological tolerance. This study focused on cytokine-NAg fusion proteins that targeted NAg to myeloid APC. Fusion proteins contained GM-CSF or the soluble extracellular domain of M-CSF as the N-terminal domain and the encephalitogenic 69-87 peptide of MBP as the C-terminal domain. GMCSF-NAg and MCSF-NAg fusion proteins were approximately 1000-fold and 32-fold more potent than NAg in stimulating antigenic proliferation of MBP-specific T cells, respectively. The potentiated antigenic responses required cytokine-NAg covalent linkage and receptor-mediated uptake. That is, the respective cytokines did not potentiate antigenic responses when cytokine and NAg were added as separate molecules, and the potentiated responses were inhibited specifically by the respective free cytokine. Cytokine-dependent targeting of NAg was specific for particular subsets of APC. GMCSF-NAg and MCSF-NAg targeted NAg to DC and macrophages; conversely, IL4-NAg and IL2-NAg fusion proteins, respectively, induced an 1000-fold enhancement in NAg reactivity in the presence of B cell and T cell APC. GMCSF-NAg significantly attenuated severity of EAE when treatment was completed before encephalitogenic challenge or alternatively, when treatment was initiated after onset of EAE. MCSF-NAg also had significant tolerogenic activity, but GMCSF-NAg was substantially more efficacious as a tolerogen. Covalent GMCSF-NAg linkage was required for prevention and treatment of EAE. In conclusion, GMCSF-NAg was highly effective for targeting NAg to myeloid APC and was a potent, antigen-specific tolerogen in EAE.

SUBMITTER: Blanchfield JL

PROVIDER: S-EPMC2830126 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC.

Blanchfield J Lori JL Mannie Mark D MD

Journal of leukocyte biology 20100301 3

Cytokine-NAg fusion proteins represent an emerging platform for specific targeting of self-antigen to particular APC subsets as a means to achieve antigen-specific immunological tolerance. This study focused on cytokine-NAg fusion proteins that targeted NAg to myeloid APC. Fusion proteins contained GM-CSF or the soluble extracellular domain of M-CSF as the N-terminal domain and the encephalitogenic 69-87 peptide of MBP as the C-terminal domain. GMCSF-NAg and MCSF-NAg fusion proteins were approxi ...[more]

PMID: 20007248

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Project description:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.

Dataset Information

A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC.

Publications

A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC.

Similar Datasets

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