Engineered perturbations to define B cell entry, competition, and function in intestinal immunity and inflammation

The National Institute of Allergy and Infectious Diseases awarded Seattle Children's Hospital $911,271 on August 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanisms regulating integration of engineered B cells in intestinal immunity and inflammation.

The research aims to develop a B cell-based immunotherapy platform for treatment of inflammatory bowel disease and related immune-mediated diseases. The project focuses on long-lived plasma cells, terminally differentiated B cells that reside in the intestinal lamina propria and secrete antibodies for extended periods. Preliminary data show that B cells engineered to express B cell receptors reactive to gut-localized microbial antigens are preferentially retained in gut tissues; the research will investigate whether this feature can be leveraged to produce gut-resident plasma cells capable of sustained biologic production. This approach targets a clinical need: current IBD therapies including anti-TNF agents fail in approximately 40 percent of patients and cause serious adverse events, while recombinant IL-10 showed limited efficacy partly due to inadequate intestinal bioavailability.

The award is obligated at $911,271 with a period of performance from August 4, 2026, through July 31, 2031. Work is performed in Seattle, Washington.

Abstract

~2.4 million people in the united states have inflammatory bowel disease (IBD), a chronic immune-mediated condition encompassing crohn's disease and ulcerative colitis. A major limitation of current IBD therapies is systemic toxicity due to on- and off-target effects. Anti-TNF therapies, though widely used, fail in ~40% of patients and can cause serious adverse events, such as pulmonary infections, autoimmune dermatological disorders, and malignancy. Recombinant IL-10, despite strong anti-inflammatory properties and success in murine studies showed limited efficacy in clinical trials for a number of reasons, including inadequate intestinal bioavailability. As such, there are significant efforts to durably target therapeutic agents directly to the inflamed intestine. A potential breakthrough for localized biologic delivery in the GUT is use of engineered long-lived plasma cells, terminally differentiated B cells that reside in specific tissue niches including the intestinal lamina propria. These cells secrete antibodies for extended periods, making them an ideal platform for sustained therapeutic protein delivery. B cell activation and differentiation are regulated by B cell receptor engagement, and interactions with cognate helper T cells that provide cytokine signals to support plasma cell differentiation. Our preliminary data show that B cells engineered to express bcrs reactive to GUT-localized microbial antigens are preferentially retained in GUT tissues, and we hypothesize that this feature could be leveraged to produce GUT-resident plasma cells capable of sustained biologic production. Our long term goal is to develop a B cell-based immunotherapy platform for treatment of IBD and related immune-mediated diseases. The primary objective in this application is to investigate the mechanisms regulating integration of engineered B cells into the host immune response, their impact on local tissue homeostasis and inflammation, and their persistence as therapeutic plasma cells. Our rationale for the proposed work is that uncovering these mechanisms has the potential to be quickly translated into therapies for ibds. Based on strong preliminary data, we will conduct three specific aims: (1) engineering B cells for small and large intestine targeting, and (2) therapeutic delivery of immunomodulators for treatment of IBD. Our approach is innovative in its use of BCR specificity to direct therapeutic B cells to disease-relevant tissues, and its integration of cellular engineering, immunology and translational modeling. The proposed work is significant because IT will establish new insights into the interaction and communication between commensal microbes and immune cells in the GUT environment and identify potential targets for therapeutic intervention in conditions of chronic intestinal inflammation.