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Leiden, Netherlands

van Noort J.M.,Delta Crystallon BV | van den Elsen P.J.,VU University Amsterdam | van den Elsen P.J.,Leiden University | van Horssen J.,VU University Amsterdam | And 4 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2011

For the development of novel central nervous system (CNS) drugs to promote neuroprotection, it is helpful to gain a better understanding of natural neuroprotective phenomena. Microglia play key roles in endogenous neuroprotective pathways and their activation is a common theme in several neurodegenerative disorders. Yet, while it is widely appreciated that activated microglia can have neuroprotective qualities, their contribution to tissue destruction and neurodegeneration within the CNS is equally obvious. This apparent duality in microglial functions renders it difficult to determine whether microglial activation under certain conditions is something to counteract, or to support. Also, it is far from clear which microglial functions support neuroprotection, and which support destruction. Here, we review evidence that a special phenomenon in multiple sclerosis (MS) patients offers a unique possibility to study polarized protective functions of microglia. During MS, small clusters of activated microglia frequently emerge throughout normalappearing white matter. Several lines of evidence suggest that these clusters, which are referred to as preactive MS lesions, represent a reversible first stage in the development of inflammatory, demyelinating MS lesions. Progression onto this final destructive stage may occur but, importantly, does not seem to be inevitable. Instead, resolution of preactive lesions is probably the rule rather than the exception. For as long as preactive lesions remain non-infiltrated by peripheral lymphocytes, they reflect a local neuroprotective and reparative response. A critical factor in the emergence of preactive lesions is oligodendrocyte stress, which leads to accumulation of factors such as small heat shock proteins. At least some of these can induce an immune-regulatory response in neighboring microglia. A closer understanding of the molecular make-up of preactive MS lesions, of the signals which cause microglial activation, and of the protective mediators produced by microglia in this context, will help uncover novel clues for neuroprotective therapeutic strategies with relevance for clinical applications well beyond the field of MS alone. © 2011 Bentham Science Publishers. Source

Peferoen L.,VU University Amsterdam | Kipp M.,RWTH Aachen | van der Valk P.,VU University Amsterdam | van Noort J.M.,Delta Crystallon BV | And 2 more authors.
Immunology | Year: 2014

Communication between the immune system and the central nervous system (CNS) is exemplified by cross-talk between glia and neurons shown to be essential for maintaining homeostasis. While microglia are actively modulated by neurons in the healthy brain, little is known about the cross-talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin-forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross-talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration. © 2013 John Wiley & Sons Ltd. Source

Amor S.,VU University Amsterdam | Amor S.,Blizard Institute of Cell and Molecular Science | Peferoen L.A.N.,VU University Amsterdam | Vogel D.Y.S.,VU University Amsterdam | And 4 more authors.
Immunology | Year: 2014

Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases. © 2013 John Wiley & Sons Ltd. Source

Delta Crystallon B.V. | Date: 2011-07-14

The invention relates to a biodegradable microparticle having a diameter between 0.2 and 3.5 micrometer and comprising a pharmaceutically effective amount of at least one small heat-shock protein that induces IL-10 production in macrophages, said small heat-shock protein comprising an amino acid sequence identity of at least 50% to any of the sequences listed as SEQ ID NOs: 1 and 12-26.

Van Noort J.M.,Delta Crystallon BV | Bsibsi M.,Delta Crystallon BV | Nacken P.,Delta Crystallon BV | Gerritsen W.H.,VU University Amsterdam | And 2 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2012

There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune-regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. © 2012 Elsevier Ltd. All rights reserved. Source

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