Lesley Probert - Academia.edu (original) (raw)

Papers by Lesley Probert

Journal of Immunology, Dec 15, 2009

A role for macrophage IκB kinase in the mucosal adjuvant activity of edema toxin for sublingual v... more A role for macrophage IκB kinase in the mucosal adjuvant activity of edema toxin for sublingual vaccines (46.2)

Journal of Medicinal Chemistry, Mar 16, 1999

Anti-inflammatory Proposed target Design and synthesis of potent cyclic analogues and mimetics of... more Anti-inflammatory Proposed target Design and synthesis of potent cyclic analogues and mimetics of myelin basic protein epitope MBP 87-99 for suppression of experimental allergic encephalomyelitis (EAE). Proposed mechanism of action Interference of the peptide in the formation of the trimolecular complex major histocompatibility complex (MHC)-peptide-T-cell receptor. Potential therapeutic indications Multiple sclerosis (autoimmune diseases). Proposed therapeutic intervention Small cyclic peptides, mimetics.

Neuroscience, May 1, 1981

We report the presence of two regulatory peptides, substance P and vasoactive intestinal polypept... more We report the presence of two regulatory peptides, substance P and vasoactive intestinal polypeptide (VIP), in the ureter and their localisation by both light-and electron-microscopy to autonomic nerves. VIP-and substance P-like immunoreactive nerves showed, in general, a similar anatomical distribution in the various layers of the ureter. Immunoreactive nerves were observed running along the smooth muscle coat, parallel to muscle bundles, around blood vessels and in the submucosa, particularly beneath the epithelium. In addition, scattered VIP-like immunoreactive ganglion cells and nerve fibres were seen in adventitial ganglia around the most distal part of the ureter and ureter-bladder junction in the cat. The guinea-pig ureter contained principally substance P-like immunoreactivity, whereas the cat ureter possessed mainly VIP-like material. The distribution of adrenergic and cholinergic nerves was compared with those containing peptides. Peptide-containing nerves had a more extensive distribution than adrenergic ones, which were mainly associated with blood vessels; however, cholinergic nerves were often localised in the same areas as those possessing peptides. Conventional electron microscopy revealed that separate p-type (peptidergic) and cholinergic nerve terminals were frequently present in the same nerve bundles, although in the cat ureter some 50% of the p-type profiles contained a mixed population of vesicles, characteristic of both cholinergic and p-type nerves. VIP-and substance P-like immunoreactivity were also localised at the ultrastructural level by means of a gold-labelled goat-antirabbit serum. HISIQCHEMICAL and ultrastructural studies have demonstrated the presence of numerous types of nerves in the ureter (

Oxidative Medicine and Cellular Longevity, May 12, 2020

CNS inflammation is a major driver of MS pathology. Differential immune responses, including the ... more CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immunemediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

Genomics, Aug 1, 2010

The brain responds to injury and infection by activating innate defense and tissue repair mechani... more The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer's disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-β signaling pathways that have been associated with neuroprotection as well as a neurodegeneration mediator, TRPM7. Further, for each disease model, we discovered collections of differentially expressed genes that provide novel insight into the individual pathology and its associated mechanisms. Our data provide a resource for exploring the complex molecular mechanisms that underlie brain neurodegeneration and a new approach for identifying generic and disease-specific targets for therapy.

Gastroenterology, Apr 1, 1983

Neurology, Apr 18, 2017

Objective: To test the hypothesis that chronic demyelination is associated with accelerated cellu... more Objective: To test the hypothesis that chronic demyelination is associated with accelerated cellular senescence. Background: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease affecting the CNS. Evidence suggests that age-related neurodegenerative processes drive disability progression in the progressive phases of MS, but the exact mechanisms are poorly understood. Cell senescence (CS) is an age-dependent process, known to be accelerated by chronic inflammation. Except for its beneficial role in preventing damaged cells from becoming oncogenic, it is thought that accelerated CS contributes to loss of function associated with aging and neurodegenerative disease. Design/Methods: The cuprizone model was used to induce demyelination in mice. The rotarod test and forelimb grip strength were used for functional assessments. Iba-1, MBP, GFAP, APP immunohistochemistry were used to quantify microglial/macrophage activation, demyelination, astrogliosis and axonal damage. γH2AX was used as a marker of DNA damage response (DDR). Senescent glial cells were detected with senescence-associated β-galactosidase (sen-β-Gal) histochemistry. All stains were quantified in the corpus callosum, in a blinded manner using image analysis software. Results: After 16 weeks of cuprizone administration there was extensive callosal demyelination and astrogliosis and significant ongoing axonal damage whereas microglial/macrophage activation had returned to control levels. Cuprizone-treated mice had developed brain atrophy as their brain weight was decreased by 8% (P Conclusions: Our study provides evidence of accelerated CS in demyelinating lesions. The accelerated CS along with the ongoing axonal damage and functional impairment seen in our model support the role of CS in the pathogenesis of disability progression under conditions chronic demyelination. Study Supported by: This work is supported by a research grant from the Multiple Sclerosis Trials Collaboration (MSTC), UK Disclosure: Dr. Papadopoulos has received personal compensation for activities with Bayer Hellas, Novartis, Genesis Pharma, and Sanofi-Genzyme as a speaker and for serving on scientific advisory boards. Dr. Karamita has nothing to disclose. Dr. Mitsikostas received personal compensation for activities with Allergan, Amgen, Bayer Schering, Eli Lilly, EMD Serono, Novartis, and Teva as a consultant. Dr. Gorgoulis has nothing to disclose. Dr. Probert has nothing to disclose. Dr. Nicholas has received personal compensation for activities with Genzyme, Roche, Novartis, and Biogen.

Frontiers in Immunology, Sep 9, 2022

Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect ... more Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect neural tissues but also peripheral immune tolerance mechanisms towards self. Together with antigen-specific T cells, myeloid cells are main effector cells in CNS autoimmune diseases such as multiple sclerosis, but the relative contributions of blood-derived monocytes and the tissue resident macrophages to pathology and repair is incompletely understood. Through the study of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein 35-55 (OM-MOG), we show that peripheral maturation of Ly6C hi CCR2 + monocytes to Ly6C hi MHCII + PD-L1 + cells is sufficient to reverse spinal cord inflammation and demyelination in MOG-induced autoimmune encephalomyelitis. Soluble intradermal OM-MOG drains directly to the skin draining lymph node to be sequestered by subcapsular sinus macrophages, activates Ly6C hi CCR2 + monocytes to produce MHC class II and PD-L1, prevents immune cell trafficking to spinal cord, and reverses established lesions. We previously showed that protection by OM-peptides is antigen specific. Here, using a neutralizing anti-PD-L1 antibody in vivo and dendritic cell-specific Pdl1 knockout mice, we further demonstrate that PD-L1 in nondendritic cells is essential for the therapeutic effects of OM-MOG. These results

Journal of Neuroimmunology, Sep 1, 1998

Gastroenterology, Nov 1, 1983

PubMed, 1981

Advances in immunocytochemistry, particularly at the electron microscope level, have enabled us t... more Advances in immunocytochemistry, particularly at the electron microscope level, have enabled us to establish further details of the ultrastructural appearance of endocrine cells and autonomic nerves of the gastrointestinal tract. Its contribution can be summarised as follows: a)validation of previously recognised endocrine cell types. b) Recognition of sub-groups within endocrine cells and autonomic nerve cell types previously included within one single type (e.g. D1 cells and p-type autonomic nerves). c) Discrimination of molecular forms now known to be stored in morphologically distinguishable secretory granules or parts thereof (e.g. pro-glucagon and glucagon in A cells and gut and antral gastrin-producing cells). Advances in the techniques and the accurate quantification of the end products will enable us to recognise changes in gastrointestinal tract diseases in man.

Neuroscience, Aug 1, 2015

Tumor necrosis factor (TNF) is the prototypic proinflammatory cytokine. It is central to host def... more Tumor necrosis factor (TNF) is the prototypic proinflammatory cytokine. It is central to host defense and inflammatory responses but under certain circumstances also triggers cell death and tissue degeneration. Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases, particularly those affecting the central nervous system (CNS). The reported contradictions may result from lack of precision in discussing TNF. TNF signaling comprises at minimum a two-ligand (soluble and transmembrane TNF) and tworeceptor (TNFR1 and TNFR2) system, with ligands and receptors both differentially expressed and regulated on different cell types. The ''functional multiplicity'' this engenders is the focus of much research, but there is still no general consensus on functional outcomes of TNF signaling in general, let alone in the CNS. In this review, evidence showing the effects of TNF in the CNS under physiological and pathophysiological conditions is placed in the context of major advances in understanding of the cellular and molecular mechanisms that govern TNF function in general. Thus the roles of TNF signaling in the CNS shift from the conventional dichotomy of beneficial and deleterious, that mainly explain effects under pathological conditions, to incorporate a growing number of ''essential'' and ''desirable'' roles for TNF and its main cellular source in the CNS, microglia, under physiological conditions including regulation of neuronal activity and maintenance of myelin. An improved holistic view of TNF function in the CNS might better reconcile the expansive experimental data with stark clinical evidence that reduced functioning of TNF and its dominant pro-inflammatory receptor, TNFR1, are risk factors for the development of multiple sclerosis. It will also facilitate the safe translation of basic research findings from animal models to humans and propel the development of more selective anti-TNF therapies aimed at selectively inhibiting deleterious effects of this cytokine while maintaining its essential and desirable ones, in the periphery and the CNS.

Cytokine, 1999

Tumour necrosis factor α (TNF-α) is a pleiotrophic cytokine synthesized primarily by macrophages ... more Tumour necrosis factor α (TNF-α) is a pleiotrophic cytokine synthesized primarily by macrophages and monocytes, which exerts a variety of biological activities during inflammatory responses, immune reactions, and wound healing. Within the central nervous system (CNS), the basal levels of TNF-α are almost undetectable, but increase after neurological insults. Using transgenic mice expressing high levels of TNF-α in the CNS,

Cellular and Molecular Life Sciences, Aug 1, 1984

In recent years, distinct changes in regulatory peptides have been found in a number of gastroint... more In recent years, distinct changes in regulatory peptides have been found in a number of gastrointestinal diseases. Grass sickness is a fatal disease of horses for which the etiology has yet to be fully ascertained. In this study, the peptide-containing nerves and ganglionic and mucosal endocrine cells of the ileum, colon and rectum were investigated in horses with sub-acute or chronic grass sickness and compared with normal controls using immunocytochemistry, at both the light and electron microscopical levels, and radioimmunoassay. A substantial loss of both peptide-containing cells and nerves was found in all of the sick horses, particularly in the ileum. Electron microscopy revealed marked degeneration of nerves in the gut wall. Fibers containing granules immunostained for substance P or VIP, using the immunogold staining technique, underwent extensive degranulation in grass sickness, with the formation of multiple vacuoles. Radioimmunoassay of peptide content also showed that the most drastic changes occurred in the ileum. For example, VIP content was significantly reduced from 109 +/- 19.8 (mean +/- SEM) pmoles/g in controls to 6.8 +/- 1.4 pmoles/g in grass sickness (p less than 0.001) and substance P from 65.9 +/- 8.1 to 31.3 +/- 9.5 (p less than 0.02). These results may have applications in the diagnosis and treatment of grass sickness.

Bioorganic & Medicinal Chemistry Letters, Dec 1, 2000

ÐIn this report the rational design, synthesis and pharmacological properties of an amide-linked ... more ÐIn this report the rational design, synthesis and pharmacological properties of an amide-linked cyclic antagonist analogue of the guinea pig myelin basic protein epitope MBP 72À85 are described. Design of the potent cyclic analogue was based on 2D NOESY nuclear magnetic resonance and molecular dynamics studies carried out in the linear antagonist Ala 81 MBP 72À85. The cyclic antagonist completely prevented the induction of experimental allergic/autoimmune encephalomyelitis when coinjected with linear and cyclic agonist analogues MBP 72À85 and cyclo(2±9)MBP 72À85 .

The Journal of Urology, Aug 1, 1983

Four peptides-vasoactive intestinal polypeptide, substance P, somatostatin and a peptide-like avi... more Four peptides-vasoactive intestinal polypeptide, substance P, somatostatin and a peptide-like avian pancreatic polypeptide-have been found in nerves of the human male genitalia using highly sensitive and specific methods of immunocytochemistry and radioimmunoassay. Five other peptides (met-enkephalin, leu-enkephalin, neurotensin, bombesin and cholecystokinin-8) were absent. Vasoactive intestinal polypeptide was the most abundant peptide, its highest concentration being in the proximal corpus cavernosum. Immunoelectron microscopy localized this peptide to large (97 ± 20

Clinical Science, Feb 1, 1982

Medical RwaPrch Society Bccauec sulpiride is the n m t epecific DA antagonist and aCmperidcme doe... more Medical RwaPrch Society Bccauec sulpiride is the n m t epecific DA antagonist and aCmperidcme does not cross the bhcdbrain barrier, it is likely that their antinatriuretec action is a renal effect. mwever the lower urine aR excretion in the rabbits in whnn natriuresis was reduced suggests that c-es in urine W are semndaty to changes in kaa excretion; indeed urine W is mainly formed in the tutules fran circulating DOPA and is unlikely to have access to the r-DA receptor. i bpgninergic nerves have been aernnStr$ted in the renal cortex; their m t a n c e in t?a excretian can bar be a s s e d by repeat-the W e expeciments after denervath of the kidneys. 86 DOW DIE?l o D I I l l 8 W T R I C T I Q ullp BLOOD PRB88vIII IN B88HTIAL-Im A DOUBLE BLIND MRWTIEBD-8 OVLU TUIAL U81110 8 u l l BODIUY AND PLACK80. 0.A. Madryor, N.D. Yukandu. 1.11. h t , D.Y. I l d o r , J.Y. C u e 0. Il-olla, Y. S q u i r u , Chuing C r c n o Ilmpital Medical B c b o o l , London, BmglW.