Supersuppressive-Induced Regulatory T-Cell Populations
Abstract
This proposal is directly focused on studies that leverage immunological approaches to prevent and treat inflammatory bowel disease (IBD). IBD is a more encompassing term that includes two more widely recognized diagnoses: ulcerative colitis (UC) and Crohn’s disease (CD). The number of both diagnoses is increasing. For example, from 1999 to 2015, the number of U.S. adults with IBD rose from 2 million to 3 million. This is a 50% increase. To date, there is no cure for IBD. Immune regulation of the gut is extremely complex. The gastrointestinal immune system must maintain the ability to both maintain tolerance towards food and the beneficial microflora of the gut while mounting a rapid response against pathogens. In the heathy state (i.e., absence of intestinal inflammation) gut homeostasis, or balance, is maintained by suppressing excessive immune responses to foreign antigens from gut non-pathogenic microbiota, self-antigens, and food antigens while synchronously mounting an appropriate response to pathogenic microbes. IBD develops when this delicate balance is tilted out of equilibrium with too much inflammation, or the body’s immune system generating too much pro-inflammatory response. It is the primary responsibility of regulatory T cells to maintaining this critical equilibrium by discriminating between harmless (e.g., dietary compounds and intestinal microbes) and harmful stimuli (e.g., pathogens). This capacity to maintain/restore balance establish regulatory T cells as the “master regulators” of intestinal balance. In fact, numerous animal studies have identified regulatory T cell deficiency as an important contributor to IBD. However, the unresolved central critical question to be addressed in this proposal is: What is the exact regulatory T cell phenotype critical for immune regulation and therefore appropriate for IBD treatment? This proposal utilizes a proprietary combination of novel bio-inspired protein mimics to easily and effectively deliver antibodies intracellularly to CD4 T cells. This is critical since although naturally occurring regulatory T cell can be removed from patients and expanded outside the body, these naturally occurring regulatory T cells make up only a very small population (~2%) of circulating immune cells. Using these bio-inspired mimics, we can transform CD4 T cells, which constitute approximately 15% of circulating immune cells, into a super-suppressive regulatory T cell population that also expands rapidly outside the body. They also remain stably active over several months in model animal studies. The development of a stable, rapidly expandable, super-suppressive regulatory T cell phenotype will find widespread application in IBD. We propose that bio-inspired antibody delivery will generate super-suppressive regulatory T cells and that these new regulatory T cells will provide symptomatic relief and durable remission when used as a cell-based therapy in IBD animal models. To accomplish this overarching hypothesis, this proposal has three major aims: Aim 1 will evaluate three major functions of these new super-suppressive regulatory T cells including their phenotype, stability (plasticity), and suppressive activity. They will also be evaluated in a humanized mouse model. Aim 2 moves the project toward translation by defining the similarities and differences between human and mouse super-suppressive regulatory T cells generated following antibody delivery. These essential studies will provide fundamental comparisons and establish important benchmarks for the more broadly used mouse models in Aim 3. Aim 3 expands therapeutic testing rigor using established all-mouse models of IBD. They include an acute and chronic model, allowing us to better capture the disease complexity associated with IBD pathogenesis. We expect the results of this proposal to set the stage for preclinical studies. Given the widely recognized dysfunction of regulatory T cells associated
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010536
Entities
People
- Gregory N Tew
Organizations
- United States Army
- University of Massachusetts Amherst