April 11, 2018
Nine Outstanding Investigators Receive Funding for Innovative Research on Lupus Causes, Pathways, and New Treatment Development
Today, the Lupus Research Alliance announced nine new Novel Research Grants to support paradigm-changing lupus research. To conquer the complexity of lupus, the Novel Research Grants explore lupus from many perspectives, testing new theories about what causes lupus and why it has such a varied and widespread effect in the body.
Many of this year’s grantees are probing new avenues for drug development that would specifically target the cells and molecular pathways that go awry in lupus but leave healthy systems intact. Others are pursuing exciting translational studies that bridge the critical gap between basic science discoveries and clinical research in people living with lupus—often using existing chemicals or drugs that potentially can be rapidly moved toward clinical trials.
Charting a Molecular Roadmap in Lupus
Betsy Jo Barnes, PhD, The Feinstein Institute for Medical Research
Turning Down an Autoimmune Inheritance
Scientists know that for many people some of the risk for lupus is genetic—that is, inherited through their family line. The gene for interferon regulatory factor 5 (IRF5), a key player in the immune system, has been strongly linked to a higher risk for lupus. This means that some versions of the IRF5 gene are more likely to be found in people with lupus, although carrying the high-risk gene does not guarantee that a person will develop lupus. Dr. Barnes wants to understand how these different, high-risk versions of IRF5 help turn a healthy immune system into one that drives an autoimmune attack that leads to lupus. With her Novel Research Grant, she will compare IRF5 in people who carry high-risk versions of the IRF5 gene but do not have lupus with IRF5 in healthy people with low-risk versions of the gene. This study explores a very early stage in lupus development and may reveal why the immune system is triggered to begin an autoimmune attack.
What this study means for people with lupus
Dr. Barnes’ research focuses on people who are at high risk of developing lupus because of their genes, yet who have healthy immune systems and no signs of autoimmunity. If she finds differences in IRF5 that help steer the immune system down a path toward lupus, her study may reveal new targets for the treatment or, even, the prevention of lupus.
Jason S. Knight, MD, PhD, University of Michigan
Tracing the Path to Organ Damage
Dr. Knight studies how a type of immune cell called a neutrophil contributes to lupus and its complications. In a model of lupus, he found that turning off elastase, a protein made in neutrophils, reduces autoimmunity, kidney disease, and blood clotting that can lead to strokes. Building on this intriguing discovery, Dr. Knight is now mapping out the molecular pathways that neutrophil elastase uses to damage the kidneys, heart, and blood vessels in lupus. This innovative research project will create a solid foundation for the development of drugs that target elastase as a potential lupus treatment.
What this study means for people with lupus
Dr. Knight has identified a new player in the development of lupus and its complications—neutrophil elastase. His Novel Research Grant will reveal whether elastase is a good target for the development of a new type of treatment for people with lupus that can protect against autoimmune responses, kidney disease, and blood clotting events.
Ziaur Rahman, MD, PhD, Pennsylvania State University College of Medicine
Retooling Antibody Factories
Dr. Rahman will use his Novel Research Grant to map out how the molecular pathways that govern antibody production areas called germinal centers differ in people with lupus from those in healthy individuals. Germinal centers are locations inside a person’s spleen and lymph nodes where immune B cells that make antibodies develop their ability to fight infections or, in the case of lupus, to attack a person’s tissues. Correcting the defects in lupus-related germinal centers could reduce or block the development of disease-causing B cells and the tissue-targeting antibodies they make that cause so much damage in people with lupus.
What this study means for people with lupus
Dr. Rahman’s research on germinal centers represents an novel target for understanding and, ultimately, treating lupus. Understanding the role of germinal centers in lupus should uncover new targets for drug development to complement existing therapies.
Developing New Treatments to Target Lupus-Causing Immune Cells Without Harming Healthy Cells
Andre Ballesteros-Tato, PhD, University of Alabama at Birmingham
Knocking out Destructive T Cells While Preserving Protectors
Dr. Ballesteros-Tato’s novel work is exploring an important interaction between two different cell types of the immune system as a new avenue for targeted drug development in lupus. Specialized immune cells—T follicular helper (Tfh) cells—act as a support system to aid and nurture the B cells, a cell type that produce self-damaging antibodies. It is these antibodies that attack the bodies of people with lupus, damaging their kidneys, brain, skin, and other organs. Dr. Ballesteros-Tato will use his Novel Research Grant to look for ways to selectively eliminate Tfh cells without knocking out other types of T cells that are part of a healthy immune system. He expects that such a treatment would, in turn, power down lupus-related B cells and block disease progression without the risk of profound immune suppression.
What this study means for people with lupus
Currently, no treatments can break the bond between Tfh cells and B cells in people with lupus. Dr. Ballesteros-Tato’s research focuses on this novel pathway and may lead to innovative directions for the development of new drugs that can add to the therapy arsenal for people with lupus.
Frances Lund, PhD, University of Alabama at Birmingham
Zeroing in on Rogue B Cells
B cells of the immune system make antibodies that are essential for the body’s defense against infectious diseases; yet, in autoimmune diseases like lupus, some B cells mistakenly go on the offense and attack the body itself instead of focusing on destroying bacteria or viruses. Dr. Lund’s ultimate goal is to improve on existing therapies that remove all B cells from a person’s immune system—such therapies treat autoimmunity but also leave patients vulnerable to new infections. With her Novel Research Grant, Dr. Lund is learning as much as she can about a unique population of B cells found in some people with lupus, but not in people without lupus. These cells (“T-bethi B cells”) have high levels of a gene-controller protein called T-bet. Understanding how these particular B cells are different could reveal new targets for safer drug therapy in lupus.
What this study means for people with lupus
By fully characterizing a specific type of B cell found in some people with lupus, Dr. Lund’s research paves the way for developing better, targeted therapies that specifically block the B cells that make lupus-related antibodies without affecting B cells that produce antibodies to fight infections.
Alessandra B. Pernis, MD, The Hospital for Special Surgery
Flipping the Off Switch
Dr. Pernis studies a unique type of B cell that has been linked to several autoimmune diseases, including lupus. These “CD11c+Tbet+” B cells have unusually high amounts of two proteins: CD11c, which hangs like a hook on the outer surface of the cell, and T-bet, a protein in the center of the cell that controls the on/off switch for some genes. CD11c+Tbet+ B cells make autoantibodies—or antibodies that mistakenly attack a person’s own tissues and, thus, trigger diseases like lupus. Dr. Pernis will use her Novel Research Grant to learn how CD11c+Tbet+ B cells are made, what molecular pathways help control the function of T-bet in the center, and how and why the cells are triggered to make autoantibodies in lupus.
What this study means for people with lupus
Dr. Pernis expects her research on CD11c+Tbet+ B cells to fill in vital pieces of the puzzle of how lupus develops. By understanding why these cells develop and how they work, she hopes to find vulnerable points that can be targeted with novel drugs that are specially designed to stop or reverse the disease process in lupus.
Repurposing Existing Drugs to Treat Lupus
Laurence Morel, PhD, University of Florida
Depriving Immune Cells of Sugar Saps Energy for Attack
In a previous study, Dr. Morel showed that drugs that make less sugar available to immune cells could stop the development of lupus in a model of the disease. Sugar is important for many cell processes, so reducing the amount available has a similar effect as when a person eats less food—the cell’s activities slow down and it has less energy to fuel an attack. The same treatment also helped immune cells taken from the blood of people with lupus act more like healthy, non-lupus immune cells. Dr. Morel hopes that this treatment might help three existing drugs – belimumab, abatacept, and ruplizumab – that have small effects in people with lupus to work better. With support from her Novel Research Grant, she will test combinations of sugar-reducing drugs like metformin, a drug widely used in diabetes, with the three lupus treatments to see whether she can slow the disease or reverse kidney damage in lupus models.
What this study means for people with lupus
Dr. Morel is pursuing a highly promising translational research project aimed at treating lupus and its complications. Because she is working with drugs like metformin that are already approved for use in people, any positive results could be readily translated into clinical trials to test the efficacy of her drug combinations in people with lupus.
Keisa Williams Mathis, PhD, University of Texas Health Science Center at Fort Worth
Nicotine Substitute May Reduce Brain Inflammation
Chronic, long-term inflammation can damage organs throughout the body, including the brain, in people with lupus. Dr. Mathis has discovered that nicotine, a chemical found in tobacco products, can reduce inflammation; however, nicotine is too toxic overall to be used as a treatment in people with lupus. In this exciting translational project, Dr. Mathis is exploring other, nontoxic molecules that might work like nicotine to heal inflammation, but without causing serious side effects. In addition, she will examine whether this type of therapy can reduce inflammation in the brain and, in turn, eliminate negative behavior changes caused by lupus.
What this study means for people with lupus
Dr. Mathis hopes to identify a new treatment for chronic inflammation in lupus that is safe, highly effective, and free of toxic side effects. Importantly, her Novel Research Grant will show whether reducing inflammation in the brain with such treatments can reverse behavioral symptoms of lupus.
Amr Sawalha, MD, University of Michigan
Taking Down the DNA Ornaments
Dr. Sawalha discovered that the DNA of particular immune cells (CD4+ T cells) changes in people with lupus as the disease progresses. In a process called “methylation,” new molecules are added to the DNA like ornaments hung on a Christmas tree. Methylation of the DNA changes the proteins that are produced and the functions that are turned up or down in the cell. These changes cause the cells to be more active and, so, more able to damage organs. He also found that a protein called EZH2 is a key participant in DNA methylation in CD4+ T cells. With his Novel Research Grant, Dr. Sawalha will delve into the effects of EZH2-led methylation in CD4+ T cells in lupus and look for ways to disrupt the methylation process in CD4+ T cells using new or existing drugs
What this study means for people with lupus
Dr. Sawalha is studying how the EZH2 protein changes the DNA in immune cells to make them more likely to launch an autoimmune attack on a person’s body. Importantly, several drugs that turn off this protein are already in clinical trials as potential cancer treatments. The results of Dr. Sawalha’s research could provide support for testing these new drugs to treat people with lupus as well.
The Lupus Research Alliance Novel Research Grant program provides three-year, $300,000 grants to investigators proposing exceptionally creative, high-risk, high-reward research on lupus and its complications. Some of the new grantees are engaged in basic research on multiple facets in the development of lupus and its complications, from the genetic variations that increase the risk for lupus in some individuals to specific lupus-related cell populations within the vast and complex immune system. These studies will fill in many gaps in our understanding and may reveal targets for innovative treatments that haven’t even been considered so far. On the other end of the spectrum, other grantees are testing whether they can quickly increase the treatment options for lupus by using existing chemicals or drugs that are already approved for or being tested in other diseases. Collectively, the promising research studies supported by the Novel Research Grants will advance our understanding of lupus and accelerate our progress toward the ultimate goal — finding a cure for all people living with or at risk for lupus.
