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    You are here : Home » MS Research News » New Discoveries » Cytokines & Chemokines

    Cytokines & Chemokines

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    Teasing apart T helper cells 29 July 2009

    CD4+ T Helper (TH) Cells
    The cytokine IL-9 promotes a multiple sclerosis-like disease in mice, according to a new study by Nowak et al. published online in the Journal of Experimental Medicine. In a related Commentary, Richard Locksley discusses the molecular and genetic regulation of cytokine production by CD4+ T helper (Th) cells and the plasticity among different Th subsets. The Commentary was published online in the Journal of Experimental Medicine on Monday, July 27th.

    Since the late 1980s, when the concept of Th1 and -2 were first introduced, several new subsets have arisen, including Th17 cells and regulatory T (T reg) cells. Recent attention has focused on a putative new Th cell subset with the propensity to secrete IL-9. But whether these "Th9" cells are truly a unique subset or whether many Th cell subsets can produce IL-9 under the right circumstances has been a matter of debate.

    Nowak and colleagues now show that a Th17-driven CNS disease was blunted in mice lacking IL-9. In vitro studies showed that IL-9 was produced primarily by Th17 and T reg cells - subsets that depend on TGF-beta for their differentiation. Thus IL-9 production may go hand-in-hand with the presence of TGF-beta rather than with a defined Th cell subset.

    Locksley, R.M., et al. 2009. J. Exp. Med. doi:10.1084/jem.20091442
    Nowak, E.C., et al. 2009. J. Exp. Med. doi:10.1084/jem.20090246

    Source: Medical News Today © 2009 MediLexicon International Ltd (29/07/09)

    Disruption of chemokine interactions may inhibit chronic inflammatory diseases like Multiple Sclerosis 06 January 2009

    Chemokines

    Research published in Nature Medicine shows that the disruption of the interactions between two small signaling proteins called chemokines by a highly potent drug-like peptide inhibits the development of atherosclerosis in mice. San Diego-based Carolus Therapeutics Inc., which has in-licensed technology based on these and other findings of collaborators at RWTH Aachen University in Aachen, Germany, is focused on the discovery and development of drugs for the treatment of atherosclerosis and other disorders triggered by acute and chronic inflammation.

    In their report, which was published online yesterday, RWTH Aachen University researchers demonstrated in a mouse model that the formation of heteromers of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5) plays a regulatory role in the development of atherosclerosis. The scientists also showed that peptides designed to disrupt the formation of PF4-RANTES heteromers inhibited the development of atherosclerosis in mice that had a genetic propensity to develop the disease. (Koenen et al., Nature Med, 2009)

    "Disrupting interactions between PF4 and RANTES is a novel approach to targeting inflammation that may lead to a new class of medications for the treatment of a variety of chronic and acute inflammatory diseases," said Jay Lichter, Ph.D., CEO of Carolus Therapeutics. "This approach could help to meet the unmet need for anti-inflammatory therapeutics for chronic diseases such as atherosclerosis, autoimmune diseases, rheumatoid arthritis, sepsis, asthma and multiple sclerosis."

    PF4 and RANTES are chemokines that are secreted by platelets. Heteromerization of PF4 and RANTES results in recruitment of monocytes (a type of white blood cell and part of the body's immune system) to the arterial wall, causing the inflammation that is characteristic of atherosclerosis.

    The RWTH Aachen University scientists characterized the structure of the PF4-RANTES interactions using NMR spectroscopy and then designed a series of peptides to disrupt those interactions. One such peptide, termed CKEY2, is comprised of sequences from the RANTES protein. CKEY2 was shown to be stable and formed the secondary structural motif found in RANTES when stabilized by disulfide bridged cysteines at both ends of the peptide. The scientists demonstrated that CKEY2 disrupts PF4-RANTES heteromer formation by binding preferentially to RANTES. In vitro assays demonstrated that CKEY2 inhibited the recruitment of monocytes to endothelial cells. Finally, the scientists demonstrated that mice that are genetically predisposed to develop atherosclerosis when fed a high fat diet did not develop chronic arterial inflammation when injected with the mouse version of the CKEY2 peptide.

    "With the efficacy of the PF4-RANTES inhibitor established in preclinical studies for atherosclerosis, we are expanding our work into pre-clinical studies in other inflammatory disease models," said Josh Schultz, Ph.D., Carolus Therapeutics' vice president of research. "Our ongoing collaboration with RWTH Aachen University involves the further exploration of chemokine interactions involved in inflammatory signaling."

    In addition to targeting PF4-RANTES heterodimers, Carolus Therapeutics has a second drug discovery program targeting the pro-inflammatory cytokine MIF (Macrophage Migration Inhibitory Factor), which has emerged as a critical mediator of innate, cell-mediated immunity, immunoregulation and inflammation. Carolus Therapeutics' scientific founders previously identified two CXC chemokine receptors as novel functional receptors for MIF. Identification of structural motifs for high affinity binding of MIF to its target receptors (Weber et al., PNAS, 2008) enables Carolus Therapeutics to expand its chemokine-interference strategies through the proprietary development of peptides, small molecules and therapeutic antibodies around MIF. The company has broad anti-MIF intellectual property that it developed as well as in-licensed from RWTH Aachen University and the Fraunhofer Society.

    Source:  Carolus Therapeutics Inc. (06/01/09)

    IL-27 Anti-Inflammation Molecule Helps Fight MS-Like Disease 12 November 2007

    An immune system messenger molecule that normally helps quiet inflammation could be an effective tool against multiple sclerosis (MS). Neurology researchers led by Abdolmohamad Rostami, M.D., Ph.D., professor and chair of the Department of Neurology at Jefferson Medical College of Thomas Jefferson University and the Jefferson Hospital for Neuroscience in Philadelphia, have found that the protein interkeukin-27 (IL-27) helped block the onset or reverse symptoms in animals with an MS-like disease.

    The results suggest that IL-27 may someday be part of a therapy to temper over-active immune responses, which are thought to be at the heart of MS, an autoimmune disease (in which the body attacks its own tissue) affecting the central nervous system. The Jefferson neuroscientists report their findings November 11, 2007 in the journal Nature Immunology.

    In MS, one of the most common neurological diseases affecting young adults, the myelin coating of nerve fibers becomes inflamed and scarred. As a result, “messages” cannot be sent through the nervous system. Dr. Rostami’s team was trying to understand the mechanisms of how immune responses damage the myelin sheath and axons in the brain.

    They had previously observed that IL-27, a signaling molecule called a cytokine, could suppress IL-17, another cytokine, and inflammation. They also knew that in other MS models, mice that lacked receptors for IL-27 developed excessive inflammation.

    Dr. Rostami, who is also director of the Neuroimmunology Laboratory in the Department of Neurology at Jefferson Medical College, Denise Fitzgerald, Ph.D., a postdoctoral research fellow in Dr. Rostami’s laboratory, and their colleagues used an animal model of MS called experimental autoimmune encephalomyelitis (EAE) for the investigation.

    When the scientists gave IL-27 to the experimental mice, it significantly suppressed active disease. They saw similar effects from IL-27 in cultured cells that were transferred into “naïve” animals, which then produced significantly milder disease. At the same time, they also showed that IL-27 enhanced the production of IL-10, a crucial anti-inflammatory cytokine.

    “We previously showed that IL-27 could suppress IL-17,” he notes. “Here we also show that IL-27 can enhance the production of IL-10. These may both be different and complementary mechanisms by which IL-27 can suppress EAE.”

    The findings suggest that increasing IL-27 concentrations might raise IL-10 levels, and help quell an over-active immune response. “This is the first time that we have direct evidence that by actively giving IL-27 like a drug, we can suppress EAE in mice.”

    Dr. Rostami explains that after an MS flare-up, patients recover from the disease, though the reasons are poorly understood. “We think that one of the ways that recovery from a disease flare-up occurs is that part of the immune system is shut off, suppressing the immune response in the brain. IL-27 appears to be crucial in this process,” he says.

    The team would like to study MS patients’ blood samples to see if similar processes are at work, Dr. Rostami notes. “If we get similar findings in human disease, then perhaps IL-27 could be used therapeutically as a compound to suppress inflammation in the brains of MS patients.”

    Source: scientificblogging.com (12/11/07)

    Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. 31 January 2007
    Li Y, Chu N, Hu A, Gran B, Rostami A, Zhang GX.
    Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

    IL-12 has long been considered important in the pathogenesis of multiple sclerosis. However, evidence from recent studies strongly supports the critical role of IL-12-related proinflammatory cytokine IL-23, but not IL-12, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of this disease.

    The role of IL-23 in the CNS immunity of multiple sclerosis patients has not been elucidated; nor is it known whether human microglia produce this cytokine. In this study we investigated the expression of IL-23p19 and p40, with its key subunit p19 as the focus, in histologically characteriSed CNS specimens from multiple sclerosis and control cases using in situ hybridiSation and immunohistochemistry.

    A significant increase in mRNA expression and protein production of both subunits of IL-23 was found in lesion tissues compared with non-lesion tissues. Double staining showed that activated macrophages/microglia were an important source of IL-23p19 in active and chronic active multiple sclerosis lesions. We also detected IL-23p19 expression in mature dendritic cells which were preferentially located in the perivascular cuff of active lesions.

    The finding that human microglia produce IL-23 was further confirmed by the inducible production of IL-23p19 and p40 in cultured human microglia in vitro upon different Toll-like receptor stimulations. Taken together, these findings on the expression of IL-23p19 in multiple sclerosis lesions may lead to a better understanding of the events culminating in human multiple sclerosis.

    Source: Brain 2007 Feb;130(Pt 2):490-501. (31/01/07)

    © Multiple Sclerosis Resource Centre

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