Trevor Owens - Academia.edu (original) (raw)

Papers by Trevor Owens

Eur J Immunol, 1996

* Department of Neurology and In experimental allergic encephalomyelitis (EAE), T cells infiltrat... more * Department of Neurology and In experimental allergic encephalomyelitis (EAE), T cells infiltrate the central nervous system (CNS) and induce inflammation. These CD4' T cells secrete interferon (1FN)-y, levels of which correlate with disease severity, and which is proposed to play a ...

Journal of Neurovirology, Feb 1, 1999

Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous ... more Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that speci®es accumulation of in¯ammatory cells within the CNS in these conditions remains a subject of active investigation. Chemokines including IP-10, GRO-a, MCP-1 are produced in EAE tissues selectively by parenchymal astrocytes, but the regulatory stimuli that govern this expression remain undetermined. The unexpected occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IFN-g) offered an opportunity to examine the spectrum of chemokine expression during immune-mediated in¯ammation in the absence of a single regulatory cytokine. We found that chemokines MCP-1 and GRO-a were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is highly expressed in the CNS of mice with an intact IFN-g gene and EAE, was strikingly absent. In vitro experiments con®rmed that IFNg selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-g for its upregulation during this model disease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-in¯ammatory cytokines.

Mol Cell Neurosci, 1998

The cytokine interferon-γ (IFNγ) is implicated in the induction of acute CNS inflammation, but it... more The cytokine interferon-γ (IFNγ) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFNγ plays in progression to chronic demyelination and neurological deficit. To address this issue, we have expressed IFNγ in myelinating oligodendrocytes of transgenic mice. MHC I immunostaining and iNOS mRNA were upregulated in their CNS, but such transgenic mice showed no spontaneous CNS inflammation or demyelination, and the incidence, severity, and histopathology of experimental autoimmune encephalomyelitis (EAE) were similar to nontransgenic controls. In contrast to control mice, which remit from EAE with resolution of glial reactivity and leukocytic infiltration, transgenics showed chronic neurological deficits. While activated microglia/macrophages persisted in demyelinating lesions for over 100 days, CD4+T lymphocytes were no longer present in CNS. IFNγ therefore may play a role in chronic demyelination and long-term disability following the induction of demyelinating disease. Because IFNγ may have neural as well as immune-infiltrating origins, these findings generate a new perspective on its role in the CNS.

Int Immunol, 1995

Sustained interaction with Th1 cells has been shown to induce IL-2 responsiveness by murine B cel... more Sustained interaction with Th1 cells has been shown to induce IL-2 responsiveness by murine B cells. This is equivalently dependent on CD40, CD54/ICAM-1 and MHC II ligation, and co-cross-linking of CD54 and MHC II in the presence of IL-5 up-regulates a functional IL-2R on B cells. We now show that IL-5 (125 U/ml) synergizes with Th1 cells to induce B cell responses to IL-2, that are maintained following T-cell removal, e.g. autonomous. Th1 help in the absence of IL-5 resulted in weak or undetectable responses following T cell removal. The mechanism of IL-5 synergy involved persistence of IL-2R beta expression following T cell removal, as opposed to enhancement of IL-2R induction or function. The level of contact-induced IL-2R expression on B cells was not itself modified by IL-5. The effects of IL-5 did not overcome the requirement for T contact signals and treatment of B cells with soluble anti-Ig did not circumvent the need for IL-5 for autonomous IL-2 responses. Consistent with the above, interaction with an IL-5-producing Th2 clone induced strong autonomous B cell responses to IL-2. Qualitative differences of Th2 help over that of Th1 may thus be attributable to their differential ability to induce autonomous B cell responsiveness to cytokines. This may be representative of events in which maintenance of cell cycle is important, as is the case in germinal centers.

Immunology, Mar 1, 1994

The mechanism whereby small resting (high buoyant density) murine B cells are induced to express ... more The mechanism whereby small resting (high buoyant density) murine B cells are induced to express interleukin-2 receptors (IL-2R) and to respond to IL-2 was addressed by staining with anti-IL-2R alpha and -IL-2R beta monoclonal antibodies (mAb), and using receptor-specific cDNA probes. Resting B cells expressed undetectable levels of both IL-2R alpha and beta chains on their surface and did not respond to IL-2, even at supra-physiological concentrations. Sepharose-coupled, but not streptavidin-cross-linked, plastic-adsorbed or soluble, anti-mu up-regulated the expression of IL-2R alpha and beta chains and mRNA to levels comparable to those seen in activated T cells. Anti-mu-stimulated B cells responded to IL-2 by incorporation of [3H]thymidine and high rate immunoglobulin (Ig) secretion. Both IL-5 (at optimal concentration) and suboptimal lipopolysaccharide (LPS; 20 ng/ml) induced surface expression of IL-2R alpha. The level of expression induced by IL-5 was equivalent to that on anti-Ig-activated B cells. Neither stimulus induced detectable expression of IL-2R beta, and neither induced B cells to respond to IL-2. IL-2R alpha expression was strongly enhanced, and low levels of IL-2R beta staining and mRNA were induced by the combination of LPS plus IL-5. LPS+IL-5-treated B cells responded to IL-2 by Ig secretion. This indicates that B cells regulate their responsiveness to IL-2 similarly to T cells, via the combined level of expression of IL-2R beta and IL-2R alpha. The synergy between IL-5 and LPS for B-cell responses shows a requirement for complementary stimuli such as would be provided by cytokines, and either cellular interaction or antigen recognition in regulation of B-cell responsiveness to IL-2.

Journal of Neuropathology and Experimental Neurology, Sep 1, 2009

Acute multiple sclerosis lesions are characterized by accumulation of T cells and macrophages, de... more Acute multiple sclerosis lesions are characterized by accumulation of T cells and macrophages, destruction of myelin and oligodendrocytes, and axonal damage. There is, however, limited information on neuroimmune interactions distal to sites of axonal damage in the T cell-infiltrated central nervous system. We investigated T-cell infiltration, myelin clearance, microglial activation, and phagocytic activity distal to sites of axonal transection through analysis of the perforant pathway deafferented dentate gyrus in SJL mice that had received T cells specific for myelin basic protein (TMBP) or ovalbumin (TOVA). The axonal lesion of TMBP-recipient mice resulted in lesion-specific recruitment of large numbers of T cells in contrast to very limited T-cell infiltration in TOVA-recipient and -naïve perforant pathway-deafferented mice. By double immunofluorescence and confocal microscopy, infiltration with TMBP but not TOVA enhanced the microglial response to axonal transection and microglial phagocytosis of myelin debris associated with the degenerating axons. Because myelin antigen-specific immune responses may provoke protective immunity, increased phagocytosis of myelin debris might enhance regeneration after a neural antigen-specific T cell-mediated immune response in multiple sclerosis.

Nature Med, 2001

The use of transgenic technology to over-express or prevent expression of genes encoding molecule... more The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on the autoimmune disease multiple sclerosis, as well as conditions in which an inflammatory response makes a secondary contribution to tissue injury or repair, such as neurodegeneration, ischemia and trauma.

Advances in Experimental Medicine and Biology, 2003

1. Adv Exp Med Biol. 2003;520:120-32. Chemokines in experimental autoimmune encephalomyelitis and... more 1. Adv Exp Med Biol. 2003;520:120-32. Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis. Babcock A, Owens T. McGill University Montreal Neurology Institute, Quebec, Canada. PMID: 12613576 ...

Interaction Between Neurons and Glia in Aging and Disease, 2007

... M. Wirenfeldt1, L. Dissing-Olesen1, AA Babcock1,2, ... However, while studies of ischemic and... more ... M. Wirenfeldt1, L. Dissing-Olesen1, AA Babcock1,2, ... However, while studies of ischemic and traumatic brain injury suggest that IL-1β has a neurotoxic role (Allan and Rothwell, 2001), whereas TNF has neurotoxic as well as neuroprotective functions (Hallenbeck, 2002), the role ...

Brain research. Brain research reviews, 2005

The distinction between immune-regulatory and effector cytokines and chemokines, and neural growt... more The distinction between immune-regulatory and effector cytokines and chemokines, and neural growth and survival factors (neurotrophins) becomes increasingly blurred. We discuss here the role of immune cytokines and chemokines as mediators of innate glial responses in the central nervous system. Glial responses to axonal degeneration in the hippocampus dentate gyrus are initiated independently of immune involvement, following transection of afferent entorhinal (perforant path) axons. The glial responses that we measure involve early microglial and somewhat later astrocyte activations. Among the earliest responses are the expression of a wide profile of chemokines, and of the cytokine tumor necrosis factor-alpha (TNFalpha). The cytokine interferon-gamma (IFNgamma) is not normally produced in the CNS, but TNFalpha levels are enhanced if it is present. Viral vector-derived IFNgamma directly induces the expression of chemokines in the CNS, in the absence of any other inflammatory event, ...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 27, 2003

Innate responses in the CNS are critical to first line defense against infection and injury. Leuk... more Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by entorhinodentate lesions. A population of Mac1/CD11b+ CD45high macrophages (distinct from CD45low microglia) was specifically detected within the lesion-reactive hippocampus by 12 hr after injury. Significant infiltration by CD3+ T cells did not occur in the denervated hippocampus until 24 hr after axotomy. A broad spectrum of chemokines [RANTES/CCL5, monocyte chemoattractant protein (MCP)-1/CCL2, interferon gamma inducible protein (IP)-10/CXCL10, macrophage inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, and MIP-2/CXCL2] was induced at this time. RANTES/CCL5 was not significantly elevated until 24 hr after axotomy, whereas MCP-1/CCL2 was significantly induced before leukocyte infiltr...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1997

The relevance of astrogliosis remains controversial, especially with respect to the beneficial or... more The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-alpha mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab,...

Science's STKE : signal transduction knowledge environment, Jan 4, 2007

Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogen... more Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in Drosophila melanogaster was implicated in the development of the nervous system. Now similar functions have been uncovered for the mammalian orthologs, the TLRs. TLRs expressed on CNS glia and neurons may recognize endogenous ligands and participate both in development and in responses associated with CNS injury.

Central Nervous System Diseases and Inflammation, 2008

Page 1. Chemokines and Autoimmune Demyelination Michaela Fux, Jason Millward, and Trevor Owens 1 ... more Page 1. Chemokines and Autoimmune Demyelination Michaela Fux, Jason Millward, and Trevor Owens 1 Introduction Autoimmune attack on the nervous system is considered the basis for multiple sclerosis (MS) (Compston ...

Research in Immunology, 1998

ABSTRACT T-cell-derived cytokines are therefore individually unnecessary and collectively insuffi... more ABSTRACT T-cell-derived cytokines are therefore individually unnecessary and collectively insufficient for microglial response. This somewhat provocative interpretation does not exclude a role for T-cell cytokines in induction of a microglial response in EAE, but it may be easier to show a non-requirement then to prove such a role. The point that emerges is that cytokine production in the CNS parenchyma is itself dependent on the prior infiltration of immune cells, and that without immune cell entry, EAE does not occur. This identifies events at the BBB, and in particular in the perivascular space, as critical immunoregulatory events in development and progression of EAE.

NeuroImmune Biology, 2001

... BV All rights reserved The Pathogenesis of Encephalitis TREVOR OWENS 1, ELISE H. TRAN 1, MINA... more ... BV All rights reserved The Pathogenesis of Encephalitis TREVOR OWENS 1, ELISE H. TRAN 1, MINA HASSAN-ZAHRAEE 1, ALICIA BABCOCK 1 ... Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P ...

Trends in Neurosciences, 1998

Members of the tumor necrosis factor/nerve growth factor receptor superfamily of cell-surface mol... more Members of the tumor necrosis factor/nerve growth factor receptor superfamily of cell-surface molecules can play the dual role of mediating either cytotoxicity or cell survival, both in the immune system and in the nervous system. A member of this superfamily, CD95 (also known as Apo1 or Fas), was initially identified in the immune system and has been shown to mediate receptor-dependent programmed cell death and to be expressed in the nervous system.

Immunology Today, 1994

Immune responses in the central nervous system (CNS) have traditionally been rega, ,;ed as repres... more Immune responses in the central nervous system (CNS) have traditionally been rega, ,;ed as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the weU-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far [rom being an immunologically privileged organ, T lymphocytes may be regular and frequent visitors to the CNS, for purposes of immune surveillance. Here, Trevor Owens and colleagues propose that the brain itself can regulate or shape immune responses therein. Furthermore, given that the immune cells may be subverted to autoirnmunity, they suggest that the study of inflammatory autoirnrnune disease in the brain may shed light on the ability of the local environment to regulate immune responses.