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On Sunday morning, Dr. Fiona Crawford, Associate Director and Vice President of the Roskamp Institute, was one of four presenters participating in a press conference titled," 'Invisible' Wounds: From Soldiers to Citizens", which focused on traumatic brain injury research working to improve the lives of citizens and soldiers. In the press conference, Dr. Crawford described the Roskamp Institute's larger traumatic brain injury research program and the Institute's work investigating anatabine's effect in laboratory models of TBI.
On Monday morning, Dr. Scott Ferguson, also of the Roskamp Institute, presented these data in a presentation titled, "TBI-Induced Spatial Memory Loss is Averted by Treatment with the Dietary Supplement Anatabine". In this study, three groups of mice were studied: One group of TBI mice was treated with anatabine, while a second group of TBI mice was untreated. A third group was comprised of normal mice. The results of the study showed that the untreated TBI mice demonstrated memory impairment; whereas, the memory of anatabine treated TBI mice was the same as normal mice. The scientists at the Roskamp Institute hypothesize that the maintenance of normal memory in TBI mice treated with anatabine is due to an inhibition of inflammation. The presentation abstract notes: "Anatabine treatment appeared to completely prevent the loss of spatial memory retention following severe TBI."
Dr. Crawford stated, "Further study of this promising treatment is warranted and will include evaluation in a mild closed head injury model as well as assessment of long term outcome from injury." Dr. Michael Mullan, President and CEO of the Roskamp Institute, explained, "Dietary supplementation to prevent memory loss after head injury has a potentially rapid development path for human use." According to the Centers for Disease Control, 1.7 million people in the United States experience TBI each year, with 80,000 survivors suffering long-term disability.
In addition to the TBI research, the Roskamp Institute presented results of its research examining the potential benefit of anatabine for alleviating symptoms associated with Multiple Sclerosis and will present new research on anatabine's effect on Alzheimer's Disease at the conference. For more information about the TBI study and the MS study, visit the Roskamp Institute's website at: http://www.rfdn.org

GLEN ALLEN, Va., Oct. 16, 2012 /PRNewswire/ -- Star Scientific, Inc. (STSI) through its wholly owned subsidiary, Rock Creek Pharmaceuticals Inc., reports that earlier in the week scientists from its research partner, the Roskamp Institute, presented results of its recent research showing that anatabine supplementation significantly reduces central and peripheral inflammation and neurological injury in an animal model of multiple sclerosis (MS). The findings were presented in New Orleans, Louisiana, at Neuroscience 2012, the 42nd annual meeting of the Society for Neuroscience, as part of a series of presentations by researchers from the Roskamp Institute on supplementation with anatabine, the active ingredient in the Company's Anatabloc® dietary supplement. Neuroscience 2012 is the world's largest and most prestigious scientific meeting dedicated to brain and neurological science. Preliminary results were reported previously on the Roskamp Institute's website; however, this recent presentation contained new and expanded findings and marked the first time these data have been presented at an international scientific convention.The presentation titled, "Amelioration of Experimental Autoimmune Encephalomyelitis by Anatabine Through Inhibition of Stat3 and NFkappaB Signaling Pathways" showed how researchers at the Roskamp Institute assessed the effects of anatabine supplementation in mice with EAE (experimental autoimmune encephalomyelitis). This condition is induced in the mice by vaccinating them with myelin, which causes an autoimmune reaction. As a consequence, there is a severe inflammatory process in the brain that causes progressive paralysis similar to that which occurs in human MS. Dietary supplementation with anatabine had a significant positive effect in reducing neurological disability and improving motor coordination of EAE mice. Results showed that 86% (13 of 15) of the mice that received anatabine supplementation had no significant hindlimb paralysis after treatment, with only 2 mice experiencing complete posterior hindlimb paralysis. In contrast, only 33% (5 of 15) of placebo-treated mice had no significant hindlimb paralysis.
In addition to the beneficial effects on motor performance, anatabine supplementation resulted in suppression of pro-inflammatory molecules induced by EAE in the spleen and serum such as IFN-gamma, IL-1 beta, IL-6, IL-17, and TNF-alpha and greatly suppressed elevated levels of IFN-gamma and TNF-alpha in the brain of EAE mice.
The Roskamp Institute also presented research at Neuroscience 2012 on the role of anatabine supplementation in facilitating recovery from traumatic brain injury (TBI). Dr. Michael Mullan, President and CEO of the Roskamp Institute, noted: "Both TBI and Multiple Sclerosis have in common massive brain inflammation. The reason anatabine supplementation looks so promising in both of these conditions is likely because, as we have previously shown, it is a potent anti-inflammatory agent. Although anatabine's anti-inflammatory activity may have different roles in each of these conditions the net result is to reduce the clinical and neuropathological consequences."
For more information about the MS research, as well as the TBI research, please visit the Roskamp Institute's website at: http://www.rfdn.org.

Endocrinology. 2012 Sep;153(9):4580-7. doi: 10.1210/en.2012-1452. Epub 2012 Jul 17.
Anatabine ameliorates experimental autoimmune thyroiditis.
Caturegli P, De Remigis A, Ferlito M, Landek-Salgado MA, Iwama S, Tzou SC, Ladenson PW.
Source
Department of Pathology, Johns Hopkins University School of Medicine, Ross 656, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. pcat@jhmi.edu
Abstract
Tobacco smoking favorably influences the course of Hashimoto thyroiditis, possibly through the antiinflammatory proprieties of nicotine. In this study we tested anatabine, another tobacco alkaloid, in a model of experimental autoimmune thyroiditis. Experimental autoimmune thyroiditis was induced by different doses of thyroglobulin, to produce a disease of low, moderate, or high severity, in 88 CBA/J female mice: 43 drank anatabine supplemented water and 45 regular water. Mice were bled after immunization and killed to assess thyroid histopathology, thyroglobulin antibodies, T(4), and thyroid RNA expression of 84 inflammatory genes. We also stimulated in vitro a macrophage cell line with interferon-γ or lipopolysaccharide plus or minus anatabine to quantitate inducible nitric oxide synthase and cyclooxygenase 2 protein expression. Anatabine reduced the incidence and severity of thyroiditis in the moderate disease category: only 13 of 21 mice (62%) developed thyroid infiltrates when drinking anatabine as compared with 22 of 23 (96%) controls (relative risk 0.59, P = 0.0174). The median thyroiditis severity was 0.5 and 2.0 in anatabine and controls, respectively (P = 0.0007 by Wilcoxon rank sum test). Anatabine also reduced the antibody response to thyroglobulin on d 14 (P = 0.029) and d 21 (P = 0.045) after immunization and improved the recovery of thyroid function on d 21 (P = 0.049). In the thyroid transcriptome, anatabine restored expression of IL-18 and IL-1 receptor type 2 to preimmunization levels. Finally, anatabine suppressed in a dose-dependent manner macrophage production of inducible nitric oxide synthase and cyclooxygenase 2. Anatabine ameliorates disease in a model of autoimmune thyroiditis, making the delineation of its mechanisms of action and potential clinical utility worthwhile.
PMID: 22807490 [PubMed - indexed for MEDLINE]

STAR SCIENTIFIC (STSI) > Anatabine 101 & The Trend Is Your Friend. 5 comments
Aug 31, 2012 3:43 PM | about stocks: STSI
8-31-2012

Dr. John L. Faessel

ON THE MARKET

Commentary and Insights

Dr.Faessel@onthemar.com

Anatabine 101

STAR SCIENTIFIC (STSI)

Where we've been & where we're going: Tobacco ― Anatabine ― Anatabloc™

There is a whole new audience out there that's just being introduced to Star's Anatabloc™ and I get contacted daily by those who wish to understand what this compound is, where it came from and where it's going? So at times, and this is one of them, we need to see where we've been to know better where we're going, such is the case for the tobacco-based alkaloid anatabine that evolved into Anatabloc™. The maxim, "The trend is your friend" rings true.

The narrative begins with tobacco; and some observations that were made near a decade ago by Johns Hopkins researchers who were studying thyroid disease in flight attendants were they found a marked reduction of the illness. Because of the confined space in airliners the exposure to tobacco smoke offered them a rare picture to study. While the Johns Hopkins researchers didn't pursue further tobacco studies because of the onus of its ills they knew that there was something "good" in tobacco.

Back in 2007, researchers at the Harvard School of Public Health found that after analyzing 11 separate studies, smokers were found to be 73% less likely to suffer from Parkinson's disease than those who didn't smoke. The study went on to state the obvious-namely that "further research could determine which chemicals are responsible for bolstering the brain against the illness." Importantly, the study also found that more years of smoking were associated with less risk.

Parallel with the above mentioned studies Star Scientific had been doing some tobacco research in search of, and finally finding the cancer-causing agents in tobacco. This is the basis for the current lawsuit against Reynolds Tobacco (RAI) that's currently before the US Supreme Court and other courts. It's been more than 10 years slog for Star to get to this point.

Next in the timeline, Stars CEO Jonnie Williams determined, in what may be a breakthrough of profound implications for mankind, that one of the 4000 chemicals in tobacco /nicotine, namely Anatabine, reduced the urge to smoke. He came to this conclusion because of the profound addictive qualities of nicotine, determining that something else in tobacco smoke, more than the nicotine was responsible for its addictive qualities. He / Star began to market the over-the-counter CigRx as an aid to help quell the urge to smoke. What Star found was that the anatabine-based compound had many/now hundreds, of other beneficial effects on those that took CigRx. Anatabloc™ was born...

This information that came out of the blue, was quite surprising to those at Star who were tracking those folks who took the CigRx compound. Harvard also did some extensive mouse studies re Anatabine and corroborated 'it's' effects. Subsequent research followed and it was found that anatabine had powerful anti-inflammatory effects. An important part of this story line occurs when Jonnie Williams wife is facing serious thyroid surgery because of his advanced thyroiditis; Williams then suggests to the Johns Hopkins surgeons that he would have his wife take some of the companies, (now determined to be anti-inflammatory) anatabine compound. Amazingly, the thyroiditis was healed. The "Ah Ha!" moment was at hand. Johns Hopkins then became very interested and they began their thyroid research.

Johns Hopkins University School of Medicine is soon to release the results of a thyroid study performed in nine clinical sites in Michigan, Texas, New Jersey, Illinois, and Florida, referred to as the Anatabloc Supplementation Autoimmune Prevention thyroid study. It is estimated by analyst Otis Bradley (Gilford Securities) that, "treatment of thyroid diseases using Star's anatabine technology could cause sales of Star's Anatabloc™ anti-inflammatory tablet (now on the market over-the-counter) to skyrocket from virtually nothing today to an annual run-rate over $400 million (with profit of $200 million or $1.00 per share) in 2013."

In the United States alone over 70 million thyroid prescriptions are written (the 4th most prescribed for the disease) at a value of about $2 billion.

Recall that at a meeting at the Roskamp Institute I attended in June 2011, Dr. Paul Ladenson, Director of the Division of Endocrinology at Johns Hopkins stated that, "aside from RCP-006 (anatabine - now Star's Anatabloc™) there is no known compound that stops thyroiditis."

Florida's Roskamp Institute also became interested in the compounds anti-inflammatory effects and they have accomplished breakthrough research quantifying anatabine (RCP-006) effects in several studies on mice and human blood. The results showed that dramatically reduces inflammation/ (RCP-006) - is more than four (4) times more effective than either Celebrex or Voltarol in reducing inflammation and was shown to be more than three (3) times more effective than Lipitor in reducing inflammation in whole human blood. These are drugs that require prescriptions from a physician and their sales are in the mega-billions: Lipitor sales in 2010 alone were $10.7 billion.

Key Peer review validating the Roskamp research then followed in the European Journal of Pharmacology under the Molecular and Cellular Pharmacology heading, titled Anatabine lowers Alzheimer's Aβ production in vitro and in vivo.

Importantly Roskamp's research was also validated by a study released by Vanderbilt University Medical Center by Dr. Paul Newhouse that was reported in the January 10 issue of Neurology. It was the first reference in the medical literature re "improvements" of cognitive impairment in human subjects with mild cognitive impairment [MCI] using nicotine. Participants also reported "feeling sharper while on the (nicotine) patch".

Under the Vanderbilt Conclusions:

1. "This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with mild cognitive impairment [MCI] over 6-months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing"

2. "The primary cognitive outcome measure [CPT] showed a significant nicotine-induced improvement."

3. "The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment."

4. "We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with mild cognitive impairment [MCI]"

It follows of course, that Anatabine / now Stars Anatabloc™ originating from nicotine could well be in the "element" in nicotine responsible for the above Vanderbilt conclusions.

Michael Mullan (MD, Ph.D.) Roskamp's Director of Research and CEO commented on the Vanderbilt study:

· Dr. Newhouse suggests that Nicotine patches may be very beneficial in individuals with mild cognitive impairment [MCI].

· "Mild cognitive impairment [MCI] is frequently regarded as a precursor to Alzheimer's disease"

· According to studies at Harvard University. "Anatabine is also a tobacco leaf-derived product, but, has no known carcinogen effects, nor does it seem to have any addictive potential."

· This recent study, using Nicotine patches for six months, has shown that individuals under the influence of Nicotine showed a 46% improvement in their "long-term memory"

· In addition Anatabine has been shown by scientists at the Roskamp Institute to be beneficial in mitigating against memory decline in animal models of Alzheimer's disease.

· Studies with Anatabine show that amyloid protein, the causative agent in Alzheimer's disease, is reduced in animal models of the disease and that this reduction parallels the improvement in memory seen with treatment with Anatabine.

· Dr. Mullan also commented (1/11/2012) in a press release from Star Scientific Inc., "Anatabine may have several advantages over nicotine in the support of memory with aging. For instance, anatabine seems to have a longer half-life in the blood, which necessitates less frequent dosing, and has shown no abuse potential in animal screening. In addition, anatabine is able to lower amyloid levels in animal models of Alzheimer's disease which become abnormally high as the disease progresses." Dr. Mullan also commented that the Roskamp Institute is actively pursuing the use of anatabine as a support for memory loss, and will be initiating human studies to explore further this potential role for anatabine."

Roskamp has just recently undertaken human Alzheimer's studies.

· Obviously, from a commercial point of view there is no patent position on nicotine, and no one could get one - so the Anatabine [Anatabloc™] alternative is attractive.

· We also know that the Anatabine stays over twice as long in the body as a cigarette delivered dose of nicotine; 8-hours vs. 4-hours.

· It therefore appears that all the beneficial effects that the nicotine patch accomplishes for subjects with mild cognitive impairment is achieved by Anatabine without the deleterious effects of addiction, potential toxicity and the numerous tobacco related medical horrors. Anatabine can also be dosed in a more effective regimen while also benefiting from the increase in half-life.

· Taken as a whole I believe this Vanderbilt study is of huge consequence in the ever improving storyline of Anatabine [Anatabloc™] in reference to Alzheimer's disease. As readers know the Roskamp Institute is well into extensive studies and trials of patients that demonstrate mild cognitive impairment, dementia and Alzheimer symptoms. Again, this study adds credence to the evolution of a possible successful treatment modality.

The market for Anatabloc™ as a reducer of low grade inflammations is of staggering proportions: the product targets chronic inflammation known to be present in a number of coronary and vascular diseases, cancers and in auto-immune diseases such as thyroid disease, diabetes, asthma, Crohn's, Irritable Bowel Syndrome, Alzheimer's, Parkinson's and arthritis, besides numerous other conditions and bodily woes ― and that includes ageing.

An excerpt from the Wikipedia epidemiology page on cardiovascular disease encapsulates much of the Roskamp research thesis: "A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein [CRP] is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease.[22] Also osteoprotegerin which involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality."

Links to the Roskamp research:

http://rfdn.org/inflammaging.html

http://www.rfdn.org/inflammaging2.html

http://www.rfdn.org/inflammaging3.html

Originally, Anatabloc™ was sold only online through the Star Scientific website and then from the Amazon and Facebook pages. More recently, General Nutrition centers (GNC) NYSE also began selling Anatabloc™ online, and from what we hear about the brisk sales (even leading to back orders) there are rumors that it won't be long before the product is carried in many more of (GNC)'s over 7,600 locations in 53 countries.

In January Star announced that it had completed a successful human clinical trial showing that Anatabloc™ lowers chronic inflammation as measured by C-reactive protein [CRP] levels in human subjects' blood. (A Google search of CRP yielded 24,000,000 results.)

Jonnie Williams, Star Scientific CEO has stated, "Anatabloc™ (anatabine) is a non-prescription anti-inflammatory product that revolutionizes inflammatory control as we know it. The studies that are already public show what the anatabine compound is capable of, and the implications for what this means to millions of individuals are limitless."

Roskamp Institute directors and biomedical researchers Michael Mullan (MD, Ph.D.) and Fiona Crawford (Ph.D.) were key members of a pioneering team of scientists who more than a decade ago discovered that the onset of Alzheimer's was directly related to the accumulation of a protein called ß-amyloid.

Roskamp testing shows that when the anatabine compound (now called Anatabloc™) that was developed by Rock Creek, a Star Scientific subsidiary, is applied to cells, ß-amyloid is reduced. The compound also appears to encourage new neuronal cell growth.

Rock Creek also filed a patent indicating that C-reactive Protein [CRP] markers are lowered when the anabatine compound is applied to cells. The provisional patent application discloses that S-(-)-anatabine positively correlates with reduction of the inflammatory activity that results in elevated blood levels of inflammation markers such as CRP. Notable is that Star's "ambassador" golfer great, tour-pro Fred Couples CRP level has dropped from 6.5 to 0.5 since he began taking Anatabloc™.

The science risk is now close to nil as there is a mass of confirming data, quotes from prestigious names, research done by influential and potent supporting scientific entities (Johns Hopkins, Harvard, Roskamp) powerful institutions funding the research (Walton Family Foundation and the National Institutes of Health [NIH] for two) and a building avalanche of anecdotal testimonials that in sum make the science a fiat accompli.

From what I hear the "word" is spreading fast in the domain of many professional sports and I'm sure 'that' will likewise filter into amateur athletics as well. Importantly, numerous and well respected coaches in many athletic disciplines are also spreading the word. Plus super celebrities and mega politicians are also taking the nutritional supplement and I expect to soon see large HMOs recommend Anatabloc™ to their members as well. In addition, the introduction of the Anatabloc™ cream is due to occur shortly and it's supposed to be to be widely marketed. So in sum, a tremendous amount of real progress on many fronts has been accomplished by Star and the wave is still building. More fun awaits... like Al Jolson (arguably in his day - the most popular, most loved, most famous and highest paid entertainer) said, "You ain't seen nothin' yet!"

Disclosure: I'm an investor in Star Scientific shares and have bought shares on the open market and have no affiliation with the company other than as a shareholder.

If you missed my previous reports-more specific in detail and scope on each of these themes send a request to: Dr.Faessel@onthemar.com

The Roskamp Institute website; http://www.rfdn.org/

To view the new Anatabloc™ website; http://anatabloc.com/

Disclosure: I am long STSI.

Additional disclosure: Disclosure: I'm an investor in Star Scientific shares and have bought shares on the open market and have no affiliation with the company other than as a shareholder.

In addition to the beneficial effects on motor performance, anatabine supplementation resulted in suppression of pro-inflammatory molecules induced by EAE in the spleen and serum such as IFN-gamma, IL-1 beta, IL-6, IL-17, and TNF-alpha and greatly suppressed elevated levels of IFN-gamma and TNF-alpha in the brain of EAE mice.

Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):315-21.
Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments.
Kollias G, Kontoyiannis D.
Source
Biomedical Sciences Research Centre, Institute for Immunology, Alexander Fleming, 14-16 Alexander Fleming Street, 166-72 Vari, Athens, Greece. g.kollias@fleming.gr
Abstract
Deregulated TNF production, be it low or high, characterizes many autoimmune diseases. Recent evidence supports a dualistic, pro-inflammatory and immune- or disease-suppressive role for TNF in these conditions. Blocking TNF in autoimmune-prone chronic inflammatory diseases may, therefore, lead to unpredictable outcomes, depending on timing and duration of treatment. Indeed, blockade of TNF in human rheumatoid arthritis or inflammatory bowel disease patients, although so far impressively beneficial for the majority of patients, it has also led to a significant incidence of drug induced anti-dsDNA production or even in manifestations of lupus and neuro-inflammatory disease. Notably, anti-TNF treatment of multiple sclerosis patients has led almost exclusively to immune activation and disease exacerbation. We discuss here recent evidence in murine disease models, indicating an heterogeneity of TNF receptor usage in autoimmune suppression versus inflammatory tissue damage, and put forward a rationale for a predictably beneficial effect of 'anti-TNFR' instead of 'anti-TNF' treatment in human chronic inflammatory and autoimmune conditions.
PMID: 12220546 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms,

Nature. 2012 Aug 23;488(7412):508-11. doi: 10.1038/nature11307.
TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.
Gregory AP, Dendrou CA, Attfield KE, Haghikia A, Xifara DK, Butter F, Poschmann G, Kaur G, Lambert L, Leach OA, Prömel S, Punwani D, Felce JH, Davis SJ, Gold R, Nielsen FC, Siegel RM, Mann M, Bell JI, McVean G, Fugger L.
Source
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Abstract
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
Comment in
Multiple sclerosis: TNF receptor 1 gene variant could explain failure of TNF-blocking drugs in multiple sclerosis. [Nat Rev Neurol. 2012]
PMID: 22801493 [PubMed - indexed for MEDLINE]

Eur Cytokine Netw. 1997 Dec;8(4):345-9.
Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells.
Coclet-Ninin J, Dayer JM, Burger D.
Source
Department of Internal Medicine, University Hospital, Geneva, Switzerland.
Abstract
Imbalance between pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) and their respective inhibitors is likely to be involved in the pathogenesis of chronic inflammatory disorders such as multiple sclerosis and rheumatoid arthritis. Increasing evidence suggests that the administration of interferon-beta (IFN-beta) displays some efficacy in the treatment of patients with relapsing-remitting multiple sclerosis. The aim of the present study was to determine the effect of IFN-beta on the production of pro-inflammatory cytokines and their inhibitors by stimulated peripheral blood mononuclear cells (PBMC). IFN-beta decreased the production of both IL-1beta and TNF-alpha in a dose-dependent manner, by up to 80% and 55%, respectively. Simultaneously, IFN-beta increased the production of IL-1 receptor antagonist (IL-1Ra) by 37% and did not modulate the release of TNF-soluble receptors (TNF-sRs) p55 and p75. Therefore, by favoring the production of cytokine antagonists over that of pro-inflammatory cytokines, IFN-beta induces an imbalance supporting anti-inflammatory processes. This effect might account for some of the therapeutic benefit of IFN-beta.
PMID: 9459613 [PubMed - indexed for MEDLINE] Free full text

J Immunol. 2011 Dec 1;187(11):5660-70. Epub 2011 Nov 4.
Pathogenic and protective functions of TNF in neuroinflammation are defined by its expression in T lymphocytes and myeloid cells.
Kruglov AA, Lampropoulou V, Fillatreau S, Nedospasov SA.
Source
German Rheumatism Research Center, a Leibniz Institute, Berlin 10117, Germany. kruglov@drfz.de
Abstract
TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.
PMID: 22058414 [PubMed - indexed for MEDLIN

Folia Med (Plovdiv). 2011 Apr-Jun;53(2):29-35.
Clinical and laboratory study of pro-inflammatory and antiinflammatory cytokines in women with multiple sclerosis.
Trenova AG, Manova MG, Kostadinova II, Murdjeva MA, Hristova DR, Vasileva TV, Zahariev ZI.
Source
Department of Neurology, Medical University, Plovdiv, Bulgaria. atrenova@yahoo.com
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system characterised with a complex system of interactions between proinflammatory and anti-inflammatory cytokines in its course.
AIM:
The aim of the present study was to investigate the serum levels of cytokines TNF-a, IFN-gamma, IL-4 and IL-10 in female patients with MS and healthy individuals, the changes occurring in the relapse and remission phases of the disease and their correlation with the severity of the neurological deficit.
PATIENTS AND METHODS:
Thirty-five women with relapsing-remitting MS were examined. The patients' age ranged between 18 and 50 years and MS was verified clinically and by magnetic resonance imaging according to the McDonald criteria. Thirteen of the patients were treated with interferon-beta-1b. The serum concentrations of TNF-a, IFN-y, IL-4 and IL-10 were determined twice - in relapse and in remission - using an enzyme-linked immunosorbent assay (ELISA). The control group consisted of 35 age-matched healthy females.
RESULTS:
The comparison of cytokine serum concentrations during the two phases of the disease showed significant elevation of the TNF-alpha serum levels in the relapse phase and of IL-4 - in the remission phase. The comparison between the patients and the healthy control subjects demonstrated statistically significant lower concentrations of TNF-a in remission patients and higher concentrations of IL-10 in relapse patients. The patients with interferon-beta-lb treatment showed different profile of cytokine secretion from the patients without interferon-beta-1b treatment. Interferon-beta-1b-treated patients showed significantly lower serum levels of TNF-a and IFN-gamma during the relapse phase and higher TNF-a and IL-10 serum levels during the remission phase compared with the untreated patients.
CONCLUSIONS:
Serum levels of TNF-a and IL-4 objectively reflect the immune response during relapse and remission of the disease. The severity of neurological deficit as estimated with the expanded disability status scale (EDSS) does not depend on the serum levels of TNF-a, IL-10 and IFN-gamma in the two phases of MS.
PMID: 21797104 [PubMed - indexed for MEDLINE]

J Neurol Sci. 1991 Aug;104(2):230-4.
Tumor necrosis factor and interleukin-1 in the CSF and sera of patients with multiple sclerosis.
Tsukada N, Miyagi K, Matsuda M, Yanagisawa N, Yone K.
Source
Department of Neurology, Shinshu University, Matsumoto, Japan.
Abstract
Serum and cerebrospinal fluid (CSF) from 31 patients with multiple sclerosis (MS) were examined to determine the levels of tumor necrosis factor (TNF) and interleukin (IL)-1 alpha (or IL-1 beta) by an enzyme-linked immunosorbent assay. TNF was detected in 29 (93.5%) of CSF from 31 cases of MS. TNF was also detectable in 100% of CSF from patients with acute relapsing MS in exacerbation. Patients with acute relapsing MS in exacerbation showed significantly higher CSF levels of TNF as compared with either those in remission or the controls (P less than 0.001 and P less than 0.0001, respectively). Increased levels of TNF were also detected in 35.5% of the MS sera, and especially in those with acute relapsing MS in exacerbation. Increased TNF levels were also frequent in the CSF and sera of patients with Guillain-Barré syndrome (GBS), which is also a demyelinating disease. No IL-1 alpha (or IL-1 beta) was detected in either CSF or sera of 31 MS patients. It is considered likely that TNF CSF levels may reflect disease activity in MS.
PMID: 1940977 [PubMed - indexed for MEDLINE]