Objective
The goal of this research is to develop engineered Tregs as a novel therapeutic approach. We will engineer Tregs to target them directly to diabetogenic CD4+ T cells.
We will:
1) Determine if multiple antigen-specific T cells can be targeted simultaneously with Tregs
2) Identify the mechanisms by which engineered Tregs suppress self-reactivity
3) Test whether engineered Tregs and T effectors can act synergistically
Background Rationale
T1D is mediated by CD4+ T cells that recognize islet autoantigens. Several cell therapies are currently under investigation for their potential in suppressing the activity of CD4+ T cells. These therapies use CD4+ regulatory T cells (Tregs), which are natural suppressors of autoimmunity, as the therapeutic cells. Approaches to engineer Tregs to target them to pancreatic islets have shown safety and efficacy in vivo. Here, we will test a novel approach for engineering Tregs.
Rationale: We have previously shown that our lab's SABR platform allows us to precisely target antigen-specific T cells. In preliminary studies, we have shown that this approach can suppress T1D in mice. Here, we will extend upon these studies to test the full therapeutic potential of engineered Tregs and determine the mechanisms that enable their therapeutic efficacy.
Description of Project
T1D is mediated by CD4+ T cells that recognize islet autoantigens. Several cell therapies are currently under investigation for their potential in suppressing the activity of CD4+ T cells. These therapies use CD4+ regulatory T cells (Tregs), which are natural suppressors of autoimmunity, as the therapeutic cells. Approaches to engineer Tregs to target them to pancreatic islets have shown safety and efficacy in vivo. Here, we present a novel approach to engineer Tregs that will allow us to engage with CD4+ T cells directly. In preliminary studies, we have shown that targeting Tregs to diabetes-inducing CD4+ T cells can protect mice from T1D. Here, we will expand upon this approach and test its full therapeutic potential in vivo. If successful, our research will develop a new strategy of engineering Tregs as an immunotherapy for T1D.
Anticipated Outcome
We anticipate that SABR-Tregs engineered to target multiple specificities provide superior protection than those targeting a single specificity. Moreover, we anticipate that SABR-Tregs have both acute and long-term suppressive effects on diabetes-inducing T cells. We also anticipate that engineering effector T cells along with Tregs can be synergistic in suppressing T1D.
Relevance to T1D
This project will develop a novel immunotherapy for Type 1 Diabetes. These results will pave the way for translating SABR engineered Tregs to humans.