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Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

ABSTRACT: Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138(+) plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1d(hi)CD5(+) regulatory B cells show resistance to depletion, and myelin-specific Foxp3(+) regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations.

SUBMITTER: Chen D

PROVIDER: S-EPMC4373313 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

Chen Ding D Blazek Monica M Ireland Sara S Ortega Sterling S Kong Xiangmei X Meeuwissen Anouk A Stowe Ann A Carter Laura L Wang Yue Y Herbst Ronald R Monson Nancy L NL

Journal of immunology (Baltimore, Md. : 1950) 20141003 10

Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experime ...[more]

PMID: 25281717

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Project description:BackgroundCirculating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.Methods and findingsWe tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/Low)HLA-DR(-)CD33(+)) compared to controls.ConclusionsTaken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage.

Project description:IntroductionMultiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). Minocycline ameliorates the clinical severity of MS and exhibits antiinflammatory, neuroprotective activities, and good tolerance for long-term use, whereas it is toxic to the CNS. Recently, the immunomodulation and neuroprotection capabilities of human bone marrow mesenchymal stem cells (hBM-MSCs) were shown in experimental autoimmune encephalomyelitis (EAE). In this study, we evaluated whether the combination of hBM-MSCs and a low-dose minocycline could produce beneficial effects in EAE mice.MethodsThe sensitivity of hBM-MSCs to minocycline was determined by an established cell-viability assay. Minocycline-treated hBM-MSCs were also characterized with flow cytometry by using MSC surface markers and analyzed for their multiple differentiation capacities. EAE was induced in C57BL/6 mice by using immunization with MOG35-55. Immunopathology assays were used to detect the inflammatory cells, demyelination, and neuroprotection. Interferon gamma (IFN-?)/tumor necrosis factor alpha (TNF-?) and interleukin-4 (IL-4)/interleukin-10 (IL-10), the hallmark cytokines that direct Th1 and Th2 development, were detected with enzyme-linked immunosorbent assay (ELISA). terminal dUTP nick-end labeling (TUNEL) staining was performed to elucidate the cell apoptosis in the spinal cords of EAE mice.ResultsMinocycline did not affect the viability, surface phenotypes, or differentiation capacity of hBM-MSCs, while minocycline affected the viability of astrocytes at a high dose. In vivo efficacy experiments showed that combined treatment, compared to the use of minocycline or hBM-MSCs alone, resulted in a significant reduction in clinical scores, along with attenuation of inflammation, demyelination, and neurodegeneration. Moreover, the combined treatment with hBM-MSCs and minocycline enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-?, TNF-?) and conversely increased anti-inflammatory cytokines (IL-4, IL-10). In addition, TUNEL staining also demonstrated a significant decrease of the number of apoptotic cells in the combined treatment compared with either treatment alone.ConclusionsThe combination of hBM-MSCs and minocycline provides a novel experimental protocol to enhance the therapeutic effects in MS.

Dataset Information

Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

Publications

Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

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