March 11, 2019 News by Jose Marques Lopes, PhD

Tecfidera May Work to Lower Relapses by Inducing Epigenetic Changes in T-cells, Study Suggests

Treating multiple sclerosis with Tecfidera induces specific genetic alterations that may reduce the levels of immune T-cells targeting the central nervous system, researchers report. Environmental stimuli may induce epigenetic changes in cells — meaning not alterations in the genes themselves, but changes in gene expression (the process by which information in a gene is synthesized to create a working product, like a protein). Epigenetic changes may induce MS development, as these alterations can cause T-cells to attack the central nervous system. One type of epigenetic change is DNA demethylation, the removal of methyl chemical groups, in which molecules involved in metabolism (such as fumarate) interact with enzymes known as DNA demethylases. This process in key for T-cell activation, function and memory, suggesting that it could be an immunomodulatory target. Fumaric acid esters were shown to be effective in MS clinical trials, leading to the approval of Tecfidera (by Biogen) for people with relapsing-remitting forms of the disease. However, their complete mechanism of action remains unclear. Aiming to address this gap, scientists at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York and the Icahn School of Medicine at Mount Sinai, recruited 98 MS patients, either previously untreated (47 people, mean age of 38.4), treated with Tecfidera (35 people, mean age of 42.3), or treated with glatiramer acetate (16 patients, mean age of 43.4) — marketed as Copaxone by Teva Pharmaceuticals, with generic forms by Sandoz (as Glatopa) and by Mylan. All patients had stable disease for at least three months, but disease duration was shortest in untreated patients — 40.4 months vs. 130 months in those given Tecfidera, and 100 months in patients using glatiramer acetate. Blood samples were collected from each participant to assess epigenetic changes in T-cells expressing the cell surface marker CD4. MS patients typically have an activated form of these cells in their blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord. Results revealed that, compared to the other two groups, treatment with Tecfidera was associated with a lower percentage of T-cells containing the CD3, CD4, and CD8 markers, as well as lower levels of subsets of T-cells expressing the CCR4 and CCR6 receptors, which are critical to T-cell migration to the gut, brain, and skin. Treatment with glatiramer acetate resulted in significantly milder alterations in T-cell percentages compared to no treatment. Researchers then found that FAEs induce excessive methylation — the addition of methyl groups — in T-cells containing CD4, compared to glatiramer acetate. Specifically, this overmethylation was observed in a micro-RNA — tiny RNA molecules than control gene expression — known as miR-21, key for the differentiation of a subset of T-cells called T helper-17 (Th17) cells and for CCR6 expression in MS mouse models. These Th17 cells are critical in tissue inflammation and destruction, and have been implicated in MS. The epigenetic effects of FAEs were subsequently validated by comparing pre- to post-treatment with Tecfidera in seven patients. In turn, in vitro (lab dish) experiments showed that FAEs act specifically on the activation of naïve T-cells — those able to respond to new pathogens to the immune system — containing the CD4 or the CD8 markers. Of note, patients with MS have shown increased miR-21 levels, particularly during acute relapses. As such, the team hypothesized that its hypermethylation by FAEs could contribute to remission and the prevention of relapses in this patient population. These results "suggest that the metabolic-epigenetic interplay in T-cells could be harnessed for therapeutic purposes," the researchers wrote, and that the immunomodulatory effect of FAEs in MS is due at least in part to the epigenetic regulation of T-cells. The researchers believe that their findings have a broader implication, beyond MS. "Our findings about therapeutically active metabolites have implications for the treatment of not only multiple sclerosis but also other autoimmune diseases, such as psoriasis and inflammatory bowel disease, which involve the same type of T-cells," Achilles Ntranos, the study’s lead author, said in a press release. "Understanding the epigenetic effect of metabolites on the immune system will help us develop several novel strategies for the treatment of autoimmune diseases, which could help patients and physicians achieve better clinical outcomes," Ntranos added. Patrizia Casaccia, the study’s senior author, concluded: "It may one day be possible to target and suppress production of the specific brain-homing T-cells that play a role in the development of MS."

February 18, 2019 News by Jonathan Grinstein

Protein That Turns Certain T-cells into Inflammatory Agents Identified in Early Study

A protein called Satb1 appears to be the "on switch" that turns a type of T-cell called Th17 from its typical protective role into one that is disease-causing, and key in the development of multiple sclerosis (MS) and other inflammatory autoimmune disorders, a study reports. These findings suggest that Satb1 may be a therapeutic target for autoimmune diseases like MS. The research article, “Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation,” was published in the journal Nature Communications. Immune cells called T-helper 17 (Th17) cells play a range of roles in immunity, including protecting against infecting pathogens — bacteria, viruses, and other microorganisms that can cause disease. But Th17 cells are also players in the development of such autoimmune diseases as MS, psoriasis, inflammatory bowel disease, and rheumatoid arthritis. This is because Th17 cells can be stimulated to become T-cells that engage in pathogenic, or disease-causing, immune programs. How Th17 cells switch from their typical and helpful immunity role to that of a pathogenic actor has not been resolved, although it is thought critical to treating inflammatory autoimmune diseases. An international team led by researchers at Osaka University and Kyoto University, in Japan, tried to identify the mechanism behind the disease-causing program of Th17 cells. To do so, they built upon previous findings showing that a protein regulator called Satb1 is important in the development of Th17 cell subsets. "We have known for some time that Satb1 is indispensable for the development of T-cells in the thymus. However, how it is involved in the regulation of pathogenic processes of Th17 cells in inflamed tissues had not been examined," Keiko Yasuda, MD, the study's lead author, said in a press release. Researchers used a standard mouse model of MS, called experimental autoimmune encephalomyelitis (EAE) mice. These animals had genetically-modified Th17 cells that lacked Satb1. Researchers tested how Th17 cells lacking Satb1 acted when subject to inflammatory conditions, and how they were stimulated to activate a "pathogenic effector program." Interestingly, these modified mice were resistant to the development of EAE, or MS-like, disease. Researchers saw fewer Th17 cells infiltrating the animals' spinal cord. Also, Th17 cells lacking Satb1 showed poorer production of key pathogenic signaling molecules in autoimmunity, notably one called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to cause localized tissue inflammation in MS and other inflammatory autoimmune diseases. Researchers went on to show that Satb1 can act as a switch between benign and pathogenic Th17 cells, depending on their exposure to healthy or inflammatory conditions. They found molecules that boost the pathogenicity of Th17 cells, such as Bhlhe40, and molecules that promote normal immune function, such as PD-1.  Of note, PD-1 is shut down when Th17 cells engage in their pathogenic effector program. These results showed Satb1 to be a key regulator of Th17 cell pathogenicity in these MS mice. Halting Th17 cells from making Satb1 may offer a way of treatting various autoimmune diseases. “Together, our findings, in addition to providing novel insights into the molecular mechanisms underlying the pathogenic program of tissue Th17 cells in mice, may help design novel immunotherapeutic approaches such as small molecule modifiers of Satb1 for the treatment of autoimmune diseases,” the researchers wrote. Future studies are needed to confirm these results in people. A previous study in people also suggested a link between Satb1 and the pathogenic function of Th17 cells in the central nervous system of MS patients. Overall, "our results suggest that manipulating Satb1 gene expression in Th17 cells could form the basis of novel treatments for various autoimmune diseases caused by Th17 cells. If we can prevent the pathogenic processes of Th17 cells, we may be able to alleviate or even eliminate disease symptoms," concluded Shimon Sakaguchi, PhD, one of the study's senior authors.

January 15, 2019 News by Jose Marques Lopes, PhD

Ocrevus Targets Certain T-Cells, Along with B-Cells, in MS Patients, Study Reports

Treatment with a single dose of Ocrevus (ocrelizumab) depleted a subset of immune T-cells within two weeks in patients with relapsing multiple sclerosis (MS) or primary progressive MS (PPMS), according to a study. The study, “Ocrelizumab Depletes CD20+ T Cells in Multiple Sclerosis Patients,” was published in the journal Cells. Autoreactive immune T-cells, which attack the body’s own tissues, have been regarded as the primary mediator of MS; however, this view has been challenged by the effectiveness of therapies targeting immune B-cells that contain the CD20 cell surface protein in reducing disease activity. One such therapy is Genentech’s Ocrevus, an anti-CD20 monoclonal antibody, which was first approved in the U.S. in 2017 for patients with relapsing MS or PPMS. Because CD20 is mainly expressed by B-cell precursors and mature B-cells, Ocrevus is often considered to selectively deplete CD20-containing B-cells. However, CD20 is also expressed by highly activated T-cells with the CD3 protein marker, characterized by the increased production of proinflammatory molecules, or cytokines. These T-cells are found in the blood, cerebrospinal fluid — the liquid surrounding the brain and spinal cord — and chronic brain lesions of MS patients, and show an elevated expression of the CD8 and CD45 markers. Off-label use of rituximab (marketed as Rituxan in the U.S. and MabThera in Europe), a lymphoma and rheumatoid arthritis treatment that also targets CD20, has been associated with the depletion of CD20-containing T-cells in MS patients. Therefore, targeting this T-cell subtype has been hypothesized as an additional mechanism for rituximab’s clinical effectiveness. However, scientists did not know whether Ocrevus, which is different from rituximab in terms of CD20 binding and cell toxicity, also depletes CD20-positive T-cells. To address this unknown, a team from Hannover Medical School in Germany analyzed blood samples of MS patients through a technique called multicolor flow cytometry prior to the first dose of Ocrevus and after two weeks, immediately before the second dose. They intended to evaluate the characteristics of the patients’ peripheral blood mononuclear cells, which include T-cells, B-cells, monocytes, and macrophages. A total of 21 patients (13 women) were included, with a median age of 43 years (range 22-65 years). Of the participants, 17 had the relapsing form of the disease for a median of 14.6 years, while four had PPMS for a median of 5.6 years. The analysis found T-cells containing CD20 and CD3 in all patients. These cells accounted for 2.4% of all CD45-expressing lymphocytes — white blood cells that include T- and B-cells — and for a significant proportion (18.4%) of all CD20 cells. Evaluation of the cells’ fluorescence intensity revealed that CD20 levels were significantly lower on T-cells than on B-cells also expressing this marker. Treatment with one dose of Ocrevus substantially lowered the levels of CD20-positive T- and B-cells within two weeks, reflected by a frequency of 0.04% and an absolute cell count decrease from 224.9 to 0.57/microliter. “Our results demonstrate that treatment with [Ocrevus] does not exclusively target B-cells, but also CD20+ T-cells, which account for a substantial amount of CD20-expressing cells,” the researchers wrote. “These findings suggest that CD20+ T-cells might play a pivotal role in the pathogenesis of MS, and we speculate that depletion of CD3+CD20+ cells by anti-CD20 monoclonal antibodies might contribute to the efficacy of anti-CD20 therapy,” they added. However, they also emphasized that the findings need to be confirmed in studies with larger groups of MS patients.

December 21, 2018 News by Patricia Inacio, PhD

Stem Cell Transplant Lessens Disability and Relapses in RRMS Patients, Phase 2 Trial Shows

Treatment with autologous hematopoietic stem cell transplant (aHSCT) led to a sustained decrease in disability and almost no clinical relapses in patients with relapsing-remitting multiple sclerosis (RRMS) who had failed to respond to prior immunosuppressive therapies, an Australian Phase 2 trial shows. Trial findings were published in the study, “Prospective phase…

October 26, 2018 News by Patricia Inacio, PhD

Infection with Common Herpes Virus Speeds MS-like Disease Onset and Progression in Primate Model, Study Reports

Infection with the most common member of the herpes virus family, called HHV-6, may pass unnoticed and without symptoms, but the very act of being infected significantly accelerated the development and progression of a multiple sclerosis-like disease in nonhuman primates, a study reports. Its findings support the role of viral infection in…

July 12, 2018 News by Patricia Inacio, PhD

Overreactive T-cells Can Transition into T-cells That Control the Immune Response, Study Shows

New research shows that overreactive and tissue-damaging T-cells can transition into regulatory T-cells that help to control the immune system’s response. These findings open the door to further understanding of the mechanism underlying this transition, knowledge that can help scientists in designing more effective, targeted immunotherapies for diseases like multiple…

April 18, 2018 News by Patricia Inacio, PhD

#AAN2018 – Ocrevus Decreases Biomarkers of MS Patients’ Nerve Cell Damage, Phase 3 Trial Shows

Genentech’s Ocrevus (ocrelizumab) reduces levels of cerebrospinal fluid biomarkers that denote nerve cell damage in multiple sclerosis patients, a Phase 3 clinical trial shows. Researchers will present the results at the American Academy of Neurology’s annual meeting in Los Angeles, April 21-27. The presentation will be titled “Interim Analysis of the…

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