Immunomodulation of EAE by alpha-fetoprotein involves elevation of immune cell apoptosis markers and the transcription factor FoxP3

Irony-Tur-Sinai, Michal; Grigoriadis, Nikolaos; Tsiantoulas, Dimitrios; Touloumi, Olga; Abramsky, Oded; Brenner, Talma

doi:10.1016/j.jns.2008.12.014

Cited by 27 publications

(15 citation statements)

References 40 publications

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“…Several evidences indicate that oligodendrocytes, the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli such as cytotoxic cytokines, antimyelin antibodies, nitric oxide, and oxidative stress. Indeed, apoptosis has been established in glial cells of both human MS patients and EAE animal models, and it has been proposed to be the crucial mechanism of MS and EAE associated dysfunctions [27, 28]. …”

Section: Resultsmentioning

confidence: 99%

The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

Savino

Pelicci

2013

Oxidative Medicine and Cellular Longevity

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Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE) experiments in p66Shc knockout mice (p66Shc−/−), knock out mice for cyclophilin-D (Cyc-D−/−), and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/−) mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

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Section: Resultsmentioning

confidence: 99%

The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

Savino

Pelicci

2013

Oxidative Medicine and Cellular Longevity

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“…There is evidence to suggest that AFP has multiple cell growth regulating, differentiating and immunosuppressive activities [54], [55]. Besides serving as a transporter of vitamin-D, VDBP plays an important role in response to tissue injury and a variety of immune and inflammatory roles related to actin scavenging, leukocyte chemotaxis and macrophage activation [56].…”

Section: Discussionmentioning

confidence: 99%

Proteomics Mapping of Cord Blood Identifies Haptoglobin “Switch-On” Pattern as Biomarker of Early-Onset Neonatal Sepsis in Preterm Newborns

et al. 2011

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BackgroundIntra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns.Methodology/Principal FindingsWe studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1st-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood (“switch-on pattern”) as opposed to non-EONS newborns who had near-absent “switch-off pattern” (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A Bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of “antenatal IAI exposure” as latent variable. This was then subjected to 2nd-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage.Conclusions/SignificanceAntenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.

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“…In fact, supernatant from hAEC culture can inhibit both innate and adaptive immune cells (Li et al, 2005). For example, hAECs produce alpha-fetoprotein, a protein that reduces immune cell reactivity and suppresses neuroinflammation in a mouse model of multiple sclerosis (Irony-Tur-Sinai et al, 2009). Furthermore, hAECs secrete macrophage inhibitory factor, which inhibits neutrophil and macrophage migration and natural killer cell-mediated cytolysis (Li et al, 2005).…”

Section: The Potential For Stem Cell Therapy Following Strokementioning

confidence: 99%

Post-stroke inflammation and the potential efficacy of novel stem cell therapies: focus on amnion epithelial cells

Broughton¹,

Lim²,

Arumugam³

et al. 2013

Front. Cell. Neurosci.

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Ischemic stroke is a debilitating disease for which there are currently no effective treatments besides the clot-buster, tissue plasminogen activator (t-PA), which is administered to less than 10% of patients due to a limited (4.5 h) time window of efficacy. Thus, there is an urgent need for novel therapies that can prevent or reverse the effects of stroke-induced brain injury. Recent encouraging reports have revealed that stem cells derived from human tissue, including embryonic, induced pluripotent, neural, and mesenchymal cells, can rescue injured brain tissue and improve functional recovery in experimental models of stroke. However, there are potentially major limitations to each of these types of stem cells that may ultimately prevent or restrict their use as viable mainstream treatment options for stroke patients. Conversely, stem cells derived from the placenta, such as human amnion epithelial cells (hAECs), appear to have several important advantages over other stem cell lineages, in particular their non-tumorigenic and non-immunogenic characteristics. Surprisingly, so far hAECs have received little attention as a potential stroke therapy. This brief review will firstly describe the inflammatory response and immune cell involvement following stroke, and then consider the potential for hAECs to improve stroke outcome given their unique characteristics. These actions of hAECs may involve a reduction of local inflammation and modulation of the immune response, promotion of neural recovery, differentiation into neural tissue, re-innervation of lost connections, and secretion of necessary cytokines, growth factors, hormones and/or neurotransmitters to restore cellular function.

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Immunomodulation of EAE by alpha-fetoprotein involves elevation of immune cell apoptosis markers and the transcription factor FoxP3

Cited by 27 publications

References 40 publications

The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

Proteomics Mapping of Cord Blood Identifies Haptoglobin “Switch-On” Pattern as Biomarker of Early-Onset Neonatal Sepsis in Preterm Newborns

Post-stroke inflammation and the potential efficacy of novel stem cell therapies: focus on amnion epithelial cells

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