1: Exp Neurol. 2008 May;211(1):214-26. Epub 2008 Feb 14.
Combined treatment with atorvastatin and minocycline suppresses severity of EAE.
Luccarini I, Ballerini C, Biagioli T, Biamonte F, Bellucci A, Rosi MC, Grossi C, Massacesi L, Casamenti F.
Department of Pharmacology, University of Florence, Viale Pieraccini n. 6, Florence, Italy.
Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process. Statins are effective in the treatment of MS animal models and are promising candidates for future treatment. Minocycline ameliorates clinical severity of experimental autoimmune encephalomyelitis (EAE) and exhibits several anti-inflammatory and neuroprotective activities. In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with myelin oligodendrocyte protein (MOG). Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, demyelination and axonal loss. Stereological analysis revealed that the combined treatment significantly guarded against neuroinflammation and neurodegeneration. Moreover, a significant suppression of anti-MOG antibody production in animals treated with the two medications was found. In conclusion, our findings prove that this combination of drugs is neuroprotective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.
Publication Types:
PMID: 18346732 [PubMed - indexed for MEDLINE]
- 2: Am J Physiol Renal Physiol. 2008 Feb;294(2):F440-9. Epub 2007 Dec 19.
Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat.
Krmer S, Wang-Rosenke Y, Scholl V, Binder E, Loof T, Khadzhynov D, Kawachi H, Shimizu F, Diekmann F, Budde K, Neumayer HH, Peters H.
Department of Nephrology and Center for Cardiovascular Research, Charit Universittsmedizin Berlin, Charit Campus Mitte, Humboldt University, Berlin, Germany.
Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg.kg(-1).body wt(-1)) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38%), systolic blood pressure (-16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (-61 and -24%), transforming growth factor-beta1 overexpression (-41 and -47%), collagen I deposition (-53 and -65%), cell proliferation (-90 and -76%), and leukocyte number (macrophages -52 and -53%; lymphocytes -58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dl, urea -66.7 mg/day, and creatinine clearance +0.13 ml.min(-1).100 g body wt(-1)). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease toward chronic glomerulosclerosis, tubulointerstitial fibrosis, and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e., proteinuria, extracellular matrix accumulation, renal cell proliferation, and inflammatory cell infiltration.
Publication Types:
PMID: 18094032 [PubMed - indexed for MEDLINE]
- 3: Arch Neurol. 2008 Feb;65(2):199-204. Epub 2007 Dec 10.
Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial.
Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ.
Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. aminag@lsuhsc.edu
OBJECTIVE: To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing-remitting multiple sclerosis (RRMS) having breakthrough disease activity. DESIGN: Open-label, 7-month trial. SETTING: Louisiana State University Health Sciences Center, Shreveport. PATIENTS: Fifteen patients with RRMS taking interferon beta-1a with breakthrough disease activity took doxycycline for 4 months. Patients underwent monthly neurologic examination, magnetic resonance imaging of the brain using triple-dose gadolinium, and safety blood work. INTERVENTIONS: Ongoing treatment with intramuscular interferon beta-1a plus oral doxycycline, 100 mg daily, for 4 months. MAIN OUTCOME MEASURES: The primary end point was gadolinium-enhancing lesion number change, and the secondary end points were relapse rates, safety and tolerability of the combination of interferon beta-1a and doxycycline in patients with MS, Expanded Disability Status Scale score, serum matrix metalloproteinase-9 levels, and transendothelial migration of monocytes exposed to serum from patients with RRMS. RESULTS: Combination of doxycycline and interferon beta-1a treatment resulted in reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P < .001 for both). Only 1 patient relapsed. Multivariate analyses indicated correlations between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. Transendothelial migration of monocytes incubated with serum from patients with RRMS undergoing combination therapy was suppressed. Adverse effects were mild; no adverse synergistic effects of combination therapy or unexpected adverse events were reported. CONCLUSIONS: Combination of intramuscular interferon beta-1a and oral doxycycline treatment was effective, safe, and well tolerated. Controlled clinical trials in larger cohorts of patients with MS are needed to evaluate the efficacy and tolerability of this combination. Trial Registration clinicaltrials.gov Identifier: NCT00246324
Publication Types:
PMID: 18071030 [PubMed - indexed for MEDLINE]
- 4: Turk J Pediatr. 2007 Jul-Sep;49(3):274-7.
Doxycycline in autoimmune central nervous system disorders in children: an in vitro study.
Anlar B, Senbil N, Gven A.
Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Tetracyclines have antiinflammatory properties. To test the in vitro effect of doxycycline in autoimmune neurological disorders of childhood, peripheral blood lymphocytes from multiple sclerosis (n=11), acute disseminated encephalomyelitis (n=12), and control patients (epilepsy and headache, n=12), all aged 5-17, were examined for proliferation, migration, and apoptosis after culture with doxycycline, concanavalin A and myelin basic protein for 48 hours. Doxycycline increased proliferation in the control group, and less in the multiple sclerosis group but not in the acute disseminated encephalomyelitis group (p<0.03). It increased apoptosis in multiple sclerosis patients (p<0.02). According to this preliminary study, doxycycline might have immunomodulatory effects in children, justifying future studies with larger and more homogeneous patient groups.
Publication Types:
PMID: 17990580 [PubMed - indexed for MEDLINE]
- 5: Arch Physiol Biochem. 2007 Jun;113(3):124-30.
Systemic infections in multiple sclerosis and experimental autoimmune encephalomyelitis.
Tauber SC, Nau R, Gerber J.
Department of Neurology, Georg-August-University, Gttingen, Germany.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It has been suggested that viral and bacterial infections contribute to the pathogenesis of MS. This review will give an overview about the influence of viral and bacterial infections on MS and experimental autoimmune encephalomyelitis (EAE). It will focus on bacterial infections and will also emphasise therapeutic consequences such as the impact of antibiotic treatment on the course of EAE. In summary, a growing body of evidence suggests that systemic infections are a risk factor for the initiation of autoimmune processes including the induction of acute events in MS. Experimental and clinical data strongly suggest early treatment of bacterial infections in MS patients to avoid aggravation and relapse.
Publication Types:
PMID: 17922308 [PubMed - indexed for MEDLINE]
- 6: Curr Opin Gastroenterol. 2007 Nov;23(6):667-72.
Hygiene, microbial diversity and immune regulation.
Guarner F.
Digestive System Research Unit, Ciberehd, University Hospital Vall d'Hebron, Barcelona, Spain. fguarner@vhebron.net
PURPOSE OF REVIEW: Sanitation, antibiotics and vaccines have done more to extend life expectancy than any other medical innovation. Concern exists, however, about the link between hygiene and increased incidence of immune-mediated disorders. RECENT FINDINGS: Studies confirm higher prevalence of asthma and allergic diseases in urban areas and developed countries rather than rural areas and developing countries. There is an inverse association between family size and disease. The debate over whether infection precipitates or prevents immune dysregulation remains a contentious one. Our knowledge about the microbial composition of the intestinal ecosystem is expanding rapidly with the introduction of molecular techniques. Differences in gut bacteria between health and atopy or inflammatory bowel disease are repeatedly reported. Recent data in inflammatory bowel disease suggest reduced species diversity and temporal instability of the gut microecosystem. The gut is a major site for induction of regulatory T cells, which secrete immunosuppressive cytokines. Not only infections, but also some commensals induce regulatory pathways, which seem to be functionally deficient in multiple sclerosis, allergies and inflammatory bowel disease. SUMMARY: Changes in lifestyle leading to decreased exposure to certain nonpathogenic species that are important for the development of immunoregulatory mechanisms are probably associated with increased incidence of some immune-mediated diseases, such as allergies and inflammatory bowel disease.
Publication Types:
PMID: 17906445 [PubMed - indexed for MEDLINE]
- 7: Infection. 2007 Oct;35(5):383-5; author reply 386. Epub 2007 Sep 19.
Comment on:
Antimicrobial treatment of multiple sclerosis.
Stratton CW, Wheldon DB.
Publication Types:
PMID: 17882356 [PubMed - indexed for MEDLINE]
- 8: Infection. 2007 Oct;35(5):370-3. Epub 2007 Aug 25.
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Gangrenous, hemorrhagic, bullous cellulitis associated with pseudomonas aeruginosa in a patient with Waldenstrm's macroglobulinemia.
Falagas ME, Pappas VD, Michalopoulos A.
Alfa Institute of Biomedical Sciences, 9 Neapoleos Street, Marousi, 151 23, Athens, Greece. m.falagas@aibs.gr
BACKGROUND: Patients with Waldenstrm's macroglobulinemia may manifest several types of skin lesions. We present our experience with a patient with the disease that adds to the literature on the topic. CASE DESCRIPTION: A 57-year-old man with history of multiple sclerosis and Waldenstrm's macroglobulinemia was admitted to the intensive care unit in shock. His family members reported that the patient had complained of fever and the gradual development of gangrenous, hemorrhagic, bullous cellulitis lesions on the abdomen and lower extremities for 7 days prior to his admission to the hospital. Pseudomonas aeruginosa was isolated from fluid specimens collected from the cutaneous lesions. Appropriate antimicrobial treatment including continuous intravenous administration of meropenem (6 g every 24 h) led to the cure of the infection. CONCLUSIONS: We postulate that the underlying Waldenstrm's macroglobulinemia contributed to the pathophysiology of the development of the rare skin manifestations of the infection observed in our patient.
Publication Types:
PMID: 17721738 [PubMed - indexed for MEDLINE]
- 9: J Am Acad Dermatol. 2007 Aug;57(2):189-202.
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Tuberous sclerosis complex: advances in diagnosis, genetics, and management.
Schwartz RA, Fernndez G, Kotulska K, Jozwiak S.
Department of Dermatology, New Jersey Medical School, Newark, NJ 07103, USA. roschwar@cal.berkeley.edu
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients; 6% of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The "ash leaf" macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a "Fitzpatrick patch." Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. LEARNING OBJECTIVE: After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.
Publication Types:
PMID: 17637444 [PubMed - indexed for MEDLINE]
- 10: J Neuropathol Exp Neurol. 2007 Jun;66(6):533-44.
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Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis.
Irani DN, Prow NA.
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dirani@jhmi.edu
Systemic treatment with the tetracycline derivative, minocycline, attenuates neurologic deficits in animal models of amyotrophic lateral sclerosis, hypoxic-ischemic brain injury, and multiple sclerosis. Inhibition of microglial activation within the CNS is 1 mechanism proposed to underlie the beneficial effects of the drug in these systems. Given the widening scope of acute viral encephalitis caused by mosquito-borne pathogens, we investigated the therapeutic effects of minocycline in a murine model of fatal alphavirus encephalomyelitis in which widespread microglial activation is known to occur. We found that minocycline conferred significant protection against both paralysis and death, even when started after viral challenge and despite having no effect on CNS virus replication or spread. Further studies demonstrated that minocycline inhibited early virus-induced microglial activation and that diminished CNS production of the inflammatory mediator, interleukin (IL)-1beta, contributed to its protective effect. Therapeutic blockade of IL-1 receptors also conferred significant protection in our model, validating the importance of the IL-1 pathway in disease pathogenesis. We propose that interventions targeting detrimental host immune responses arising from activated microglia may be of benefit in humans with acute viral encephalitis caused by related mosquito-borne pathogens. Such treatments could conceivably act through neuroprotective rather than antiviral mechanisms to generate these clinical effects.
Publication Types:
PMID: 17549013 [PubMed - indexed for MEDLINE]
- 11: Neurochem Int. 2007 Nov-Dec;51(6-7):333-55. Epub 2007 Apr 19.
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The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention.
Sheldon AL, Robinson MB.
Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104-4318, United States.
Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.
Publication Types:
PMID: 17517448 [PubMed - indexed for MEDLINE]PMCID: PMC2075474 [Available on 11/01/08]
- 12: Curr Med Chem. 2007;14(11):1189-97.
Microglial activation and its implications in the brain diseases.
Dheen ST, Kaur C, Ling EA.
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore 117597.
An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, prion diseases, multiple sclerosis and HIV-dementia. The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS, which normally respond to neuronal damage and remove the damaged cells by phagocytosis. Activation of microglia is a hallmark of brain pathology. However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.
Publication Types:
PMID: 17504139 [PubMed - indexed for MEDLINE]
- 13: Curr Neurol Neurosci Rep. 2007 May;7(3):223-30.
Novel oral agents for multiple sclerosis.
Burton JM, O'Connor P.
Multiple Sclerosis Clinic, Division of Neurology, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. burtonj@smh.toronto.on.ca
In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.
Publication Types:
PMID: 17488588 [PubMed - indexed for MEDLINE]
- 14: Mult Scler. 2007 May;13(4):517-26. Epub 2007 Feb 9.
The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study.
Zabad RK, Metz LM, Todoruk TR, Zhang Y, Mitchell JR, Yeung M, Patry DG, Bell RB, Yong VW.
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.
Publication Types:
PMID: 17463074 [PubMed - indexed for MEDLINE]
- 15: Cytotherapy. 2007;9(2):144-57.
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Comment in:
Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis.
Keever-Taylor CA, Browning MB, Johnson BD, Truitt RL, Bredeson CN, Behn B, Tsao A.
Department of Medicine/Division of Neoplastic Diseases and Related Disorders, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ckeever@mcw.edu
BACKGROUND: CD4(+) CD25(bright+) regulatory T cells (Treg) can be expanded to clinical doses using CD3/CD28 Ab-coated beads plus IL-2. However, this method requires high purity of the starting population to prevent overgrowth by non-regulatory T cells. Rapamycin, an agent that inhibits T-cell proliferation but selectively spares Treg, may be a means to expand Treg from less pure CD25-enriched cells. METHODS: CD25-enriched cells were prepared by a single-step immunomagnetic-selection using anti-CD25 microbeads. The cells were activated with a single addition of anti-CD3/CD28 beads and expanded in ex vivo 15-5% HS and autologous CD4(+) CD25(-) feeder cells,+/-rapamycin (0.01-20 ng/mL). IL-2 was added on day 3. Cells were rested for 2 days in ex vivo 15-5% HS and tested for phenotype, intracellular Foxp3 protein and suppressor activity. RESULTS: In the absence of rapamycin, CD25-enriched fractions expanded >17 000-fold by 21 days. Although suppressor activity was detected to day 14, it declined significantly by 21 days as non-regulatory cells expanded. The addition of rapamycin inhibited expansion of non-regulatory T cells at doses > or =1 ng/mL while increasing suppressor activity and the percentage of CD4(+) CD25(+) CD27(+) Foxp3(+) cells. Rapamycin did not enrich for Foxp3(+) cells in expanded cultures of CD4(+) CD25(-) cells. Treg were also readily expanded in cultures of CD25-enriched cells obtained from patients with multiple sclerosis in the presence of rapamycin. DISCUSSION: The addition of 1-20 ng/mL rapamycin to CD25-enriched cultures increased the purity of cells with the phenotype and function of Treg. This approach may alleviate the need for rigorous enrichment of Treg prior to activation and expansion for potential clinical use.
Publication Types:
PMID: 17453966 [PubMed - indexed for MEDLINE]
- 16: Cytotherapy. 2007;9(2):109-10.
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Comment on:
Manipulating regulatory T cells.
Barrett AJ.
Stem Cell Allotrransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, Maryland 20892, USA. barrettjj@mail.nih.gov
Publication Types:
PMID: 17453962 [PubMed - indexed for MEDLINE]
- 17: Neurobiol Dis. 2007 Mar;25(3):514-25. Epub 2007 Jan 18.
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Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation.
Maier K, Merkler D, Gerber J, Taheri N, Kuhnert AV, Williams SK, Neusch C, Bhr M, Diem R.
Neurologische Universittsklinik, Robert-Koch-Strasse 40, D-37075 Gttingen, Germany. kmaier@gwdg.de
Axonal destruction and neuronal loss occur early during multiple sclerosis, an autoimmune inflammatory CNS disease that frequently manifests with acute optic neuritis. Available therapies mainly target the inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of minocycline on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials and RGC function was monitored by measuring electroretinograms. Functional and histopathological data of RGCs and optic nerves revealed neuronal and axonal protection when minocycline treatment was started on the day of immunization. Furthermore, we demonstrate that minocycline-induced neuroprotection is related to a direct antagonism of multiple mechanisms leading to neuronal cell death such as the induction of anti-apoptotic intracellular signalling pathways and a decrease in glutamate excitotoxicity. From these observations, we conclude that minocycline exerts neuroprotective effects independent of its anti-inflammatory properties. This hypothesis was confirmed in a non-inflammatory disease model leading to degeneration of RGCs, the surgical transection of the optic nerve.
Publication Types:
PMID: 17239606 [PubMed - indexed for MEDLINE]
- 18: Infection. 2006 Dec;34(6):342-4.
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Comment in:
Long-term antibiotic treatment with roxithromycin in patients with multiple sclerosis.
Woessner R, Grauer MT, Frese A, Bethke F, Ginger T, Hans A, Treib J.
Dept. of Neurology, Westpfalz Medical Center, 67655, Kaiserslautern, Germany.
BACKGROUND: There are conflicting results concerning an association between Chlamydia pneumoniae and MS (multiple sclerosis). In the present study, we investigated a possible therapeutic option with antibiotics. PATIENTS AND METHODS: In our randomized, placebo-controlled double-blind study, 28 patients with the confirmed diagnosis of MS [61% relapsing-remitting MS (RR-MS), 32% secondary chronic-progressive MS (SP-MS) and 7% primary chronic progressive MS (PP-MS)] were treated over a time period of 12 months with three cycles of a 6-week oral antibiotic therapy with roxithromycin (300 mg per day) or placebo. RESULTS: No significant differences were observed in patients with RR-MS regarding the expanded disability status scale (EDSS) and the relapse rate when comparing treatment with roxithromycin and placebo. CONCLUSION: Our study shows that the patients with MS do not profit from a long-term antibiotic treatment with roxithromycin compared to placebo treatment. A causative connection between bacterial infections with C. pneumonia and MS therefore does seem very unlikely.
Publication Types:
PMID: 17180590 [PubMed - indexed for MEDLINE]
- 19: Infection. 2006 Dec;34(6):299.
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Comment on:
Antibiotic treatment of diseases without an evident infectious etiology.
Ruef C.
Publication Types:
PMID: 17180581 [PubMed - indexed for MEDLINE]
- 20: Int Immunopharmacol. 2006 Dec 20;6(13-14):1935-42. Epub 2006 Aug 17.
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Dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) as regulators of T cell function and targets of immunotherapy in CNS inflammation.
Reinhold D, Biton A, Pieper S, Lendeckel U, Faust J, Neubert K, Bank U, Tger M, Ansorge S, Brocke S.
Institute of Immunology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de <dirk.reinhold@medizin.uni-magdeburg.de>
The ectoenzymes dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) have been implicated in the regulation of T cell activation and function. Both DP IV and APN serve as targets of efficient enzymatic inhibitors which induce autocrine production of TGF-beta1 and subsequent suppression of T cell proliferation and cytokine release. Here, we tested the hypothesis that the simultaneous inhibition of DP IV and APN enzymatic activity on leukocytes potentiates the anti-inflammatory effect of single DP IV or APN inhibitors. Our data show that the combined application of DP IV and APN inhibitors increased suppression of DNA synthesis in human peripheral blood mononuclear cells and isolated T cells in vitro when compared to the use of a single ectopeptidase inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF-beta1 production associated with the observed immunosuppressive effects. In vivo, targeting DP IV and APN provided a potent therapeutic approach for the treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Taken together, our study suggests that combined DP IV and APN inhibition on pathogenic T cells represents a novel and efficient therapy for autoimmune disease of the central nervous system by a mechanism that involves an active TGF-beta1-mediated anti-inflammatory effect at the site of pathology.
Publication Types:
PMID: 17161346 [PubMed - indexed for MEDLINE]
- 21: Chem Biol. 2006 Nov;13(11):1227-34.
A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model.
Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S, Liu Y, Gao W, Chu A, Brinkmann V, Bruns C, Streiff M, Cannet C, Cooke N, Gray N.
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.
PMID: 17114004 [PubMed - indexed for MEDLINE]
- 22: Am J Epidemiol. 2006 Dec 15;164(12):1253; author reply 1253-4. Epub 2006 Nov 9.
Comment on:
Re: "antibiotic use and risk of multiple sclerosis".
Parratt JD, O'Riordan JI, Swingler RJ, Parratt D.
Publication Types:
PMID: 17095537 [PubMed - indexed for MEDLINE]
- 23: J Antimicrob Chemother. 2007 Jan;59(1):74-9. Epub 2006 Nov 1.
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Minocycline delays but does not attenuate the course of experimental autoimmune encephalomyelitis in Streptococcus pneumoniae-infected mice.
Herrmann I, Kellert M, Spreer A, Gerber J, Eiffert H, Prinz M, Nau R.
Department of Neurology, Georg August University, D-37075 Gttingen, Germany.
OBJECTIVES: Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), can be aggravated by a mild Streptococcus pneumoniae infection. This study was performed to assess whether treatment with antibiotics inhibiting bacterial protein synthesis reduces the detrimental effect of infection on the course of EAE. METHODS: In vitro, release of proinflammatory pneumococcal products was studied by enzyme immunoassay and western blot. Seven days after induction of EAE (prior to the onset of symptoms) mice were infected intraperitoneally with S. pneumoniae and treated either with the inhibitors of bacterial protein synthesis minocycline or rifampicin, or with the beta-lactam ceftriaxone. RESULTS: During bacterial killing in vitro, minocycline and rifampicin released lower quantities of proinflammatory bacterial products from S. pneumoniae than ceftriaxone. Mice treated with minocycline developed symptoms of EAE 1 day later than mice treated with ceftriaxone. Neither minocycline nor rifampicin therapy, however, reduced the severity of EAE in comparison with ceftriaxone treatment. CONCLUSIONS: Although statistically significant (P = 0.04), a delay of 1 day in the onset of symptoms of EAE after minocycline treatment is of minor clinical relevance. These data do not support the hypothesis of superiority of a bacterial protein synthesis inhibitor over a beta-lactam antibiotic for the treatment of concomitant infections during the latent phase of EAE or MS.
Publication Types:
PMID: 17079237 [PubMed - indexed for MEDLINE]
- 24: Cell. 2006 Sep 8;126(5):955-68.
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Comment in:
TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activate