Benaroya Research Institute at Virginia Mason

Interventional immunologyinterventional immunology and advancements of the immune tolerance network (itn) are highlighted below. Funding for the immune tolerance network (itn) was initially awarded to dr. jerry nepom at bri in 2014 by the national Institute of allergy and infectious disease (niaid) of the national institutes of health (nih). It was later renewed for a second grant cycle in 2021, providing approximately $27 million annually to support the itn. This Research consortium, established in 1999, primarily focuses on developing new tolerogenic approaches for treating and preventing diseases in three clinical areas: asthma and allergic diseases, autoimmune diseases, and immune-mediated rejection of transplanted solid organs, tissues, and cells. Bri, as the prime recipient of this grant, is responsible for managing the overall grant from niaid, including overseeing all aspects of the network's infrastructure.during this period, major activities remained diverse but continued to center around maintaining the itn's cohesive, project-focused environment, which has been highly successful in managing this large cooperative agreement grant.key outcomes during this period include:1. Leadership changes: with the changes to the overall itn leadership structure outlined in the 2021 grant application fully implemented. Dr. jerry nepom stepped down as the network director and principal investigator, and although now retired, remains involved with the itn in a senior advisor role. The primary investigator for the um1 grant is now dr. jane buckner, president of bri. She also serves on the itn steering committee and the itn network executive committee, playing an active role in tracking progress towards network goals and developing strategies to meet network objectives. The function of the network director's office at bri continues with no changes, except for a name change to the itn coordinating center. The network director position moved to dr. mark anderson at ucsf, funded through a subaward from the bri itn coordinating center. 2. The itn cross-network integration: since 2014, dr. nepom has led the itn with a strong focus on meticulous planning and collaboration across the itn's major centers, located in seattle (bri), san francisco (ucsf), durham, nc (duke), boston (bwh), atlanta (emory), and ann arbor (u of Michigan). Effective collaboration was particularly evident when, despite the global pandemic, the itn conducted its network steering committee (nsc) remotely, approving five new clinical trials during the reporting period. In 2022/2023, the itn returned to conducting in-person nsc meetings, which continued without interruption. With strong approval from niaid for the itn's overall infrastructure and the desire to keep the coordinating center operations at bri with dr. buckner, there are no planned changes throughout the current grant cycle, which extends until 2027.3. Operations and clinical trial support: the itn coordinating center at bri issued over 250 subawards during this reporting period to support 24 active itn clinical trials and numerous supporting itn mechanistic trials. An additional 22 subawards were negotiated in support of the two remaining niaid covid trials.4. Supplemental funding / partnerships: the itn coordinating center continued to focus on identifying additional opportunities for supplemental funding and funding partnerships. Negotiations for a partnership to provide partial financial support for at least one clinical trial in development are actively underway.during this reporting period, the itn also supported the contracting component for two niaid-sponsored covid-19 clinical trials funded through administrative supplements. Both trials are on track to conclude by q4 2024:(a) supplemental funding opportunities: the itn coordinating center at bri submitted two supplemental funding requests in 2022, which were carried over into 2023. These supplements account for an additional $7 million allocated to the itn program at bri during this time period. (b) partnerships: the itn continued its partnership with pharmaceutical company for partial funding for an itn study. Niaid is the clinical sponsor of this trial, which is progressing as planned for completion in q2 2024.5. Publication activity: in total, 44 itn publications were published during this reporting period in prestigious Research journals and were presented at domestic and international Research conferences. These publications represented itn Research in all therapeutic focus areas: autoimmunity, transplantation, and allergy.

Autoimmune disease Research in the down syndrome populationin october 2022, the national Institute of allergy and infectious diseases (niaid) announced a new $3.4 million-dollar five-year Research project grant (r01) to bri to study why immune responses are altered in those with down syndrome (ds).bernard khor, md, phd, in partnership with Virginia Mason pediatrician and bri researcher rebecca partridge, md, leads the r01 grant that builds on his prior findings that any given person with ds has an immune system that resembles that of a significantly older individual without ds. With this grant, he will examine the mechanisms behind advanced immune aging and explore how this impacts clinically relevant responses, such as the ability to mount an effective response to vaccination. His work is made possible by the bri biorepositories of blood and tissue samples from people with ds.in his previous studies, dr. khor and his team used mass cytometry to examine the immune systems of 28 people with ds and, through the creation of a new analytical software, showed how these immune systems share characteristics with those of much older subjects who do not have ds, as well as with individuals with certain autoimmune diseases. For the first time, a protein called il-6 was associated with changes that drive aging of the immune system.the team believes their findings may also help explain why people with ds are more likely to develop autoimmune diseases such as type 1 diabetes, celiac disease and rheumatoid arthritis.

Type one diabetes researchbri is dedicated to seeking ways to eliminate type 1 diabetes (t1d) by finding ways to predict the disease before clinical symptoms occur and to identify therapies that prevent, reverse and intervene in the disease at any stage. Bri is an international leader in type 1 diabetes Research and has investigated it for more than 36 years, starting with identification of a genetic marker for the disease. Bri supports type 1 diabetes trialnet, a national institutes of health funded clinical trial network for type 1 diabetes prevention and early treatment, serving as the trialnet hub of 18 clinical centers worldwide working with more than 150 screening and clinical Research sites. Bri is also a clinical center for the trialnet pathway to prevention study, screening relatives of people with type 1 diabetes to find out if these family members are at risk for developing diabetes. Relatives of people with type 1 diabetes are at 15 times greater risk of developing type 1 diabetes. Those who qualify have the opportunity to enroll in a prevention trial. Those with two or more autoantibodies are closely monitored for early detection of type 1 diabetes. Close monitoring of at-risk family members can reduce the chances of being diagnosed in diabetic ketoacidosis (dka), a potentially life-threatening complication. Bri scientists led by carla greenbaum, md, director of bri's center for interventional immunology, along with the trialnet consortium spent decades trying to determine how to stop t1d before it starts. Their hard work came to fruition in november 2022, when the fda approved a therapy that marked a milestone in preventing t1d. The therapy, teplizumab, can delay t1d for a median of two years. It impacts t cells in the immune system, dampening the immune response. In t1d, the immune system is attacking the insulin-producing beta cells; teplizumab helps slow the attack on these cells.and, a study led by bri's cate speake, phd, found that interventions involving il-6-targeted therapies impacted immune outcomes in people with t1d, depending on the target of the therapeutic interventions (il-6 versus il-6r) and drug concentration. The findings indicate that these therapies drive t cell changes that can influence therapeutic outcomes.also in 2022, bri scientists along with investigators at seattle children's Research Institute made a significant advance in developing a t cell therapy to t1d treat type 1 diabetes (t1d). The study, published in october 2022 in science translational medicine, outlined an approach to engineer regulatory t cells (tregs) to stop the immune cell attack on the pancreas that causes t1d.dr. Jane buckner, president of bri, and dr. david rawlings, director of the center for immunity and immunotherapy at seattle children's Research Institute, and their teams had worked toward this goal for more than ten years. First, they developed gene editing methods to manufacture human tregs, an important step for overcoming challenges with purifying and expanding tregs from blood for clinical production. This work demonstrated that engineered tregs (engtregs) were functional, suppressing the immune response in pre-clinical models of inflammatory diseases.the next step was to make these engtregs specific to the pancreas, so that they would go to the pancreas and suppress the autoimmune response that causes t1d. To do this, the scientists used their knowledge of t cell receptors (tcrs), proteins on the t cell surface that determine the target of t cells. They combined gene editing with gene transfer of tcrs to generate engtregs that specifically target the islet in the pancreas.dr. Soo jung yang in dr. buckner's lab demonstrated that these islet-specific engtregs have the capacity to suppress t cells attacking the pancreas using cell culture models of cells isolated from individuals with t1d. Dr. rawlings and his team then demonstrated that these islet-specific engtregs target the pancreas and prevent diabetes in a mouse model of diabetes. Together these findings demonstrate the therapeutic potential for islet-specific engtregs in human t1d. This Research was sponsored by a grant from the leona m. and harry b. helmsley charitable trust.viral and pollutant exposures and potential treatments for people at risk for asthma matt altman, md, mphil, who conducts asthma Research at bri and treats asthma patients at uw medicine, was senior author of a study that identified a potentially promising new asthma treatment for urban kids at risk for the disease. The study from the inner-city asthma consortium (icac) found that a therapy called mepolizumab can reduce asthma attacks among children in low-income hispanic and black communities. Mepolizumab works by blocking a protein necessary for the development of eosinophil, a type of white blood cell. In another study, published in the journal of allergy and clinical immunology, bri researchers in collaboration with seattle children's, the university of Washington school of medicine and the university of Wisconsin discovered why individuals with allergic asthma may have reduced susceptibility to covid-19 and an important mechanism by which allergic inflammation diminishes sars-cov-2 infection, despite well-known susceptibilities to other respiratory viral infections. Allergic diseases such as asthma are characterized by type-2 inflammation in the airways. Bri's naresh doni jayavelu, phd, and the Research team looked at mechanisms whereby type-2 inflammation in the airway surprisingly protects against sars-cov-2 in children. The findings also illustrate a notable mechanism of intrinsic protection against sars-cov-2. Since the study findings were based on in vitro cell culture experiments, drs. Jayavelu and altman subsequently began to investigate to what degree type-2 inflammation decreases viral replication and severe disease in a large observational cohort that was enrolled at the beginning of the pandemic to more fully understand the clinical impact of their results. This Research was funded by the national Institute of allergy and infectious diseases, part of the national institutes of health, and other sources, building on a previous study that set the groundwork for a hypothetical mechanism of protection. A separate study funded by the nih linked specific outdoor air pollutants to asthma attacks in urban children. In the study, moderate levels of two outdoor air pollutants, ozone and fine particulate matter, were associated with non-viral asthma attacks in children and adolescents who live in low-income urban areas. The study also identified associations between exposure to the two pollutants and molecular changes in the children's airways during non-viral asthma attacks, suggesting potential mechanisms for those attacks. This study was conducted by the niaid-funded inner city asthma consortium under the leadership of dr. altman along with daniel j. jackson, m.d. Of the university of Wisconsin school of medicine.the observational study is one of the first to link elevated levels of specific outdoor air pollutants in particular urban locations to distinct changes in the airways during asthma attacks not triggered by respiratory viruses, according to the investigators. The findings were published in the journal the lancet planetary health.the scientists found that asthma attacks had a non-viral cause in nearly 30% of children, two to three times the proportion seen in non-urban children, according to previously published reports. These attacks were associated with locally elevated levels of fine particulate matter and ozone in outdoor air. The investigators linked changes in the expression of specific sets of genes that play a role in airway inflammation to elevated levels of these two pollutants by analyzing nasal cell samples obtained from the children during respiratory illnesses.

Examining the immune system in health and disease bri along with collaborators at the uw published findings in the journal of experimental medicine that illustrate a novel mechanism for the role of regulatory t cells (tregs) in maintaining balance in a healthy immune system. Tregs prevent the immune system from overreacting to harmless substances and from reacting to the body's own cells, which leads to autoimmunity. While several mechanisms for how tregs suppress immune system activation have been proposed, the molecular changes that tregs induce to suppress the immune response have previously remained unclear. The new results showed that when tregs interact with cd4 effector t cells (teffs), the cells that promote an inflammatory response, they suppress protein synthesis, preventing cell division and the production of more teffs.steven ziegler, phd, bri principal investigator and co-author on the study, noted the Research furthers understanding of how tregs work in the body to maintain immune balance.dr. Buckner, also a co-author on the study, said the results further our understanding of how tregs work to control inflammation and how we can enhance them to suppress the development of autoimmune diseases.in Research published in science immunology, scientists from bri with collaborators at Pennsylvania state university college of medicine showed that thymic stromal lymphopoietin (tslp) signaling regulates germinal center (gc) function. During an infection, gcs form in the secondary lymphoid tissues, such as the lymph nodes, tonsils and spleen, among other tissues. These gcs are dynamic microenvironments that optimize antigen specificity of b cells and whose activity results in long-lived and high-affinity antibodies, which ultimately provides long-term immunity against infection. Yet, the signaling molecules that regulate gc function are still being identified.steven ziegler, phd, bri principal investigator and co-author on the study, said that in addition to identifying tslp as a novel regulator of the gc, the team was able to demonstrate how the tslp signaling pathway impacts b and t cell responses separately to regulate the gc and the magnitude and quality of antibody responses.phillip domeier, phd, bri post-doctoral scientist and co-author on the study, noted that the study could serve as a foundation for future Research on vaccines, allergies and autoimmune diseases. Bri oversees the clinical Research program at Virginia Mason medical center, uniquely combining the expertise of a world-renowned medical Research Institute with the care of a healthcare quality leader. The clinical Research program supports Virginia Mason clinical investigators in studies across a wide variety of autoimmune and immune-mediated diseases and conditions, as well as a broad range of other diseases such as cancer and cardiac disease. The clinical Research program staff annually enrolls approximately 2,264 study participants into Virginia Mason trials.established in 2023, the innovation fund award is to be given twice a year to internal recipients at bri. The objective is to facilitate development and implementation of new technologies that will advance work across our institution, through the funding of collaborative projects.. each award is to be funded from philanthropic gifts.bri's regular track and Research track faculty are award eligible. Projects are required to include two or more bri faculty and address innovations useful to multiple Research groups within the Institute. Further, it is required that the protocols and results generated in the project will be made available to all bri investigators. The first awardees, john ray, phd, and jessica hamerman, phd, developed methods to carry out large genetic screens in single cells from their respective labs and through collaboration between the systems and fundamental immunology centers. Their project brought together two major advances in genomics: single cell sequencing to profile many different cells at once, and crispr utilized to modify genes in immune cells and see their effects. Their approach allows us to understand how genes and gene variants associated with complex diseases impact the immune system as well as disease processes in human cells and animal models.