CXCL16

Scientists found that a subset of CD8+ T cells in the brain lessens the activation of microglia and limits disease pathology in a model of Alzheimer's disease. As many as 5.8 million Americans are currently living with Alzheimer's disease, a neurodegenerative condition associated with progressive cognitive decline, including loss of memory capabilities . Protein aggregates, composed of beta-amyloid or other proteins, form in the brains of individuals with Alzheimer's. These beta-amyloid plaques appear to be a significant contributor to the disease. St. Jude Children's Research Hospital scientists uncovered a subset of immune cells that appears to slow this beta-amyloid plaque accumulation and the key proteins involved in the process. The findings were published today in Nature Immunology. "People typically think of the immune system as being involved in defense from bacterial or viral infection, though there is growing interest in the role of the immune system in neurodegenerative diseases," said co-first author Jordy Saravia, Ph.D., St. Jude Department of Immunology. "We uncovered an important immune cell communication axis that is protective in an Alzheimer's disease model." Microglia are immune cells in the brain responsible for clearing beta-amyloid plaques. As Alzheimer's disease progresses, microglia can lose their capacity to remove these plaques and instead produce inflammatory mediators that may accelerate beta-amyloid plaque progression. The St. Jude team found that accumulating another subtype of immune cells, called CD8+ T cells, is essential to slow this process by interacting with microglia. This interaction, in turn, was important to limit beta-amyloid burden and preserve memory capabilities in a mouse model of the disease. "Our paper is the first to demonstrate that a subpopulation of CD8+ T cells can be protective in a mouse model of Alzheimer's disease," said co-first author Wei Su, Ph.D., St. Jude Department of Immunology. "Moving forward, we may be able to extend this work to find an effective intervention for neurodegenerative diseases." Immune cells' opposing roles in Alzheimer's disease Previous research has established complex roles for T cells and other immune system cells in Alzheimer's disease. In particular, research groups using other experimental systems have suggested that certain T cells with inflammatory functions worsen the disease. However, the St. Jude scientists showed that CD8+ T cells with suppressive features accumulate in the brains of both mouse models and patients with Alzheimer's disease, highlighting that T cells play a complex role in this disease. "We showed that CD8+ T cells can play a protective role against Alzheimer's disease pathogenesis, although there is also evidence for a contributing role," said corresponding author Hongbo Chi, Ph.D., St. Jude Department of Immunology. "Our results demonstrate the need to better understand these complex neuro-immune interactions to improve outcomes for this neurodegenerative disease." To understand how T cells were delaying symptom progression in their Alzheimer's disease model, the St. Jude group searched for the most abundant molecular interaction between CD8+ T cells and the microglia. They found a protein on the surface of CD8+ T cells, CXCR6, interacts with the protein CXCL16 expressed by microglia. A molecular handshake slows Alzheimer's disease The two surface proteins, CXCR6 and CXCL16, essentially performed a handshake between the two cells, communicating in both directions. Just like the firmness of a human handshake can convey information, so can the interaction of these two proteins on the outside of their respective cells. "We found CD8+ T cells use CXCR6 to interact with CXCL16 from microglia," Chi said. "Moreover, CD8+ T-cell accumulation, localization and function in the brain are regulated by CXCR6." The scientists determined how the handshake occurs and delays the onset of Alzheimer's disease-related pathologies. The CD8+ T cells first move next to the microglia, which are localized next to the beta-amyloid plaques. Then, the CD8+ T cells use the handshake to signal to the microglia to stop causing uncontrolled inflammation, which, in turn, slows plaque growth and symptoms in the mouse models. When the scientists deleted the gene for the CD8+ T cell's protein CXCR6, the mice developed worse Alzheimer's disease-related symptoms. This effect was partially because the CD8+ T cells without CXCR6 failed to accumulate in the brain near the microglia or plaque site. These cells also did not acquire the appropriate suppressive function. Thus, disrupting the CD8+ T cell's ability to perform the handshake prevented its protective effect against Alzheimer's disease symptoms. "We have two major findings," Chi said. "One is the crucial role of CD8+ T cells in maintaining homeostasis of the brain, thereby providing a protective role in Alzheimer's disease." Homeostasis is the process of keeping a system in a relatively stable state. In this case, the CD8+ T cells attempt to limit the disruption caused by microglia dysfunction and Alzheimer's disease-related plaques. "The other major finding is identifying the central importance of the T cell protein CXCR6 for CD8+ T-cell accumulation and function in the brain," Chi continued. "We really need to characterize these kinds of neuro-immune interactions better. Only by understanding this basic biology can we advance the field and find new treatments."

Ottawa, Canada, July 18, 2023 (GLOBE NEWSWIRE) -- Orion Biotechnology Canada Ltd. (Orion), a drug discovery and development company unlocking the therapeutic potential of previously undruggable G Protein-Coupled Receptors (GPCRs), today announced that it has successfully completed a discovery campaign against CXCR6, an undrugged small protein GPCR with the potential to provide a new and innovative form of immunotherapy treatment for solid tumor cancers. Completed in only four months, the rapid identification of this first-in-class (FIC) molecule further validates Orion’s PROcisionXTM discovery platform’s industry-leading efficiency. CXCR6 is expressed in several subsets of T cells, natural killer T cells, and bone marrow stromal cells, and the main physiological role of the CXCR6-CXCL16 axis is to activate numerous signaling pathways essential to regulating immunity. Boosting signaling through the CXCR6-CXCL16 axis in the tumor microenvironment has the potential to provide a new route to block solid tumor growth by helping to maintain anti-tumor cytotoxic T cells in an aggressive, non-exhausted state. “We are very excited about the significant progress we continue to make across our portfolio” said Dr. Ian McGowan, the company’s Chief Medical Officer. “Orion’s discovery success will allow for a new and highly differentiated strategy to drug CXCR6 for the treatment of cancer and other inflammatory diseases.” Dr. Oliver Hartley (VP Discovery) commented: “Small protein GPCRs have proven challenging to unlock using established small molecule and antibody-based approaches. This rapid success provides further evidence that Orion’s novel scientific approach can unlock previously undrugged small protein GPCRs and provides a clear illustration of the efficiency of our PROcisionXTM discovery platform.” Orion’s CEO Mark Groper remarked: “Unlocking previously intractable GPCRs represents a tremendous opportunity to develop new treatments across a broad range of therapeutic areas. Our rapid success with a new small protein GPCR marks another key milestone in our mission to deliver medicines that improve the lives of patients. The combination of our highly talented team and our PROcisionXTM platform is allowing our company to rapidly and efficiently build out a multi-product pipeline of high-value GPCR-targeted therapeutics.” About Orion Biotechnology Orion’s mission is to unlock the therapeutic potential of previously undruggable GPCRs. Orion has world-renowned expertise in GPCR pharmacology and protein engineering, and its proprietary drug discovery platform (PROcisionXTM) has been used to rapidly and efficiently advance a diversified portfolio of GPCR-targeted drug candidates for the treatment of cancer and other serious diseases. For more information, follow Orion Biotechnology on LinkedIn or visit . Ross MacLeod Orion Biotechnology Canada Ltd. +1 343.291.1032 ross@orionbiotechnology.com

Winning projects will explore new potential treatment approaches to prevent lupus from developing or prevent or slow disease progression. NEW YORK, April 20, 2023 /PRNewswire/ -- The Lupus Research Alliance (LRA) today announced the newest Lupus Mechanisms and Targets Award grant recipients. The winning four projects collectively test potential treatment approaches to prevent lupus from developing or reducing lupus disease activity. Lupus has a broad range of causes and symptoms, and these multiple approaches are important for designing customized therapies that can provide better outcomes for a wide range of patients. The LRA LMTA grants offer up to $600,000 over three years for research focusing on investigating molecular pathways or targets leading to the development of new or improved therapies for patients with cutaneous and systemic lupus erythematosus (SLE). "These four new LMTA awards support innovative lupus researchers whose work is poised to deliver much needed new information for the lupus field. We are proud to be able to offer this financial support, with the ultimate goal of improving outcomes for lupus patients," said Teodora Staeva, Ph.D., vice president and chief scientific officer of LRA. Lupus Mechanisms and Targets Award Winners Jennifer Anolik, M.D., Ph.D.; University of Rochester Medical Center Dr. Anolik will investigate if sodium-glucose cotransporter-2 (SGLT2) inhibitors – a class of drugs approved to treat type 2 diabetes and associated kidney disease – can improve outcomes in lupus nephritis, which is inflammation in the kidneys caused by lupus that affects 40 to 70 percent of lupus patients. Current treatment approaches target inflammation with little impact on fibrosis and injury. Dr. Anolik will study mice with lupus nephritis to see if SGLT2 inhibitors reduce kidney hypoxia, inflammatory CD8 T cells, and kidney injury. She will also begin to investigate the effects of treatment with SGLT2i on clinical outcomes and pathogenic CD8 T cells in the blood and urine of patients with lupus nephritis. Betsy Barnes, Ph.D.; The Feinstein Institutes for Medical Research Systemic lupus erythematosus (SLE) has heritable components that can be passed on to children through gene variants. Variants in the interferon regulatory factor 5 (IRF5) gene, which controls the production of type I interferons, can be inherited, and they increase the risk of developing SLE. Dr. Barnes has recently identified a new regulator of IRF5 function– STK25 – that turns on IRF5 in SLE immune cells. Using this award, Dr. Barnes will compare STK25 activity in healthy people with and without IRF5 gene variants and in SLE patients. She will also aim to determine how STK25 activates IRF5 in response to SLE triggers and investigate if loss of the STK25 gene protects against lupus in lupus-prone mice, which will aid future clinical trials focused on targeting STK25 and/or IRF5 as new therapeutics. Michelle Kahlenberg, M.D., Ph.D.; University of Michigan Dr. Kahlenberg recently found that abnormal activity of Hippo proteins turns on the overproduction of immune system molecules (interferons) in lupus patients' blood and skin. Dr. Kahlenberg will use this award to study whether turning off these Hippo proteins will decrease the amount of type I interferons, one of the hallmarks of cutaneous lupus and SLE. Her investigation will determine if Hippo proteins could serve as new therapeutic targets. Dr. Kahlenberg's work builds on decades of pioneering studies on type I interferons funded by the LRA. Jillian Richmond, Ph.D.; University of Massachusetts Chan Medical School T cells are immune cells that can cause lupus flares in the skin. Dr. Richmond found that skin T cells in both people and mice have a protein on their cell surface called CXCR6. The T cell CXCR6 interacts with a protein called CXCL16 on skin cells, similar to how a lock and key fit together. Dr. Richmond will use this award to determine if the CXCL16-CXCR6 interaction is important in keeping the harmful T cells in the skin of patients with cutaneous lupus. She will also investigate if targeting these two molecules will provide a lasting treatment response in pet dogs with skin lupus through a veterinary clinical trial. This project could provide new information about the molecules on the surface of lupus-causing immune cells that could be targeted to prevent or slow lupus disease progression. About Lupus Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. More than 90 percent of people with lupus are women; lupus most often strikes during the childbearing years of 15-45. Black/African Americans, Hispanic/Latino, Asians, and Native Americans are two to three times at greater risk than Caucasians. In lupus, the immune system, which is designed to protect against infection, creates antibodies that can attack any part of the body including the kidneys, brain, heart, lungs, blood, skin, and joints. About the Lupus Research Alliance The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately a cure for lupus. Because the Lupus Research Alliance's Board of Directors funds all administrative and fundraising costs, 100% of all donations goes to support lupus research programs. SOURCE Lupus Research Alliance