Objective
We propose to develop two complementary strategies to target graft-rejecting effector T cells and block inflammatory injuries to the beta cells. We will evaluate these concepts in human SC-beta cells in cell cultures and in humanized mouse models.
Background Rationale
Transplanting a foreign tissue such as pancreatic islets provokes a strong immune response. In recipients with type 1 diabetes, the per-existing autoimmune responses against the beta cells further enhances the rejection responses. Moreover, beta cell grafts are small and fragile when compared to other transplanted organs. Thus, protecting beta cells against immune rejection is a difficult challenge. Clinical islet transplant experiences show that strong immunosuppression that delete T cells and suppressing inflammatory is associated with better long-term graft function. Such strong immunosuppression regimen is often difficult for patients to tolerate.
The advent of derivation of beta cells from stem cells will not only provide a renewal source of beta cells but also offers the opportunity to engineer the beta cells to avoid immune rejection. Since each patient's immune system react to the transplanted beta cells differently, an effective beta cell immune engineering strategy will need to be able to shield the beta cells against known and unknown immune insults without causing global immunosuppression. In this proposal, we have designed our immune shielding strategies with these considerations in mind by focusing on tackling the two major drivers of islet graft rejection - T cells and inflammation.
Description of Project
Stem cell-derived beta cells (SC-beta) have entered clinical testing and early results are promising. However, commitment to life-long immunosuppression is a major barrier for patients to adopt the therapy. Current strategies to address this issue mainly focus on immune-editing to delete immunogenic traits in SC-beta. These strategies require complete removal of immunogenicity, which is difficult to achieve especially for a diverse population of patients. An effective dominant strategy is needed. Research proposed in this application aims at developing "Armored SC-beta" that can actively shield themselves against alloimmune and autoimmune rejection so that no systemic immunosuppression is needed.
Anticipated Outcome
We will design molecules that target T cells and the inflammatory mediator tumor necrosis factor alpha. We will first test the feasibility of producing these molecules in stem cell-derived beta cells followed by evaluating the efficacy of the armored beta cells in shielding themselves against graft-rejecting T cells and inflammatory insults. The demonstration of feasibility and efficacy of this strategy will provide motivations to further develop the technology for future clinical evaluations.
Relevance to T1D
The proposed project aims to advance beta cell replacement therapy for type 1 diabetes by developing stem cell derived beta cells that can shield themselves from immune attacks. If successful, this strategy may eliminate the need for life-long systemic immunosuppression and make beta cell replacement therapy safer and more appealing for a broader patient population.