The overall goal of this project is to design and implement a biomimetic artificial antigen presenting cell platform to treat Type 1 Diabetes (T1D). T1D is a life-threatening autoimmune disease affecting over 1 million Americans that occurs when the immune system destroys insulin-producing beta islet cells in the pancreas, requiring lifelong insulin replacement therapy and greatly increasing the patient?s risk of comorbidities. New treatments that halt disease and establish tolerance toward beta islets are therefore desirable. One of the most promising strategies for tolerance induction is the enhancement of regulatory T cells (Tregs). Tregs are powerful mediators of tolerance toward self-antigens but are often impaired in T1D, and therapies that strengthen their numbers and restore their function are needed. Artificial antigen presenting cells (aAPCs) directly engage and modulate T cells via Signal 1, 2, and 3 proteins conjugated to the surface or encapsulated within a particle and have the capacity to influence Treg populations. However, the vast majority of aAPCs have been designed to activate cytotoxic T cells for cancer immunotherapies and have not been widely explored in a tolerogenic context. Current ?tolerogenic? aAPCs lack critical factors supporting Treg induction and expansion and pose a risk of exacerbating the anti-diabetes immune response. We have successfully demonstrated that an aAPC platform can be used to induce Tregs. We showed that altering material properties of the aAPC core improved protein conjugation to the surface of the particle, giving it potential as an ?off-the-shelf? therapy that can be administered directly in vivo. The aAPC core also supported encapsulation of critical Treg induction factor TGF-?, and a single dose of these aAPCs given to mice led to polarization of the in vivo T cell repertoire towards Tregs. We therefore hypothesize that encapsulated and surface-bound tolerogenic cues are critical for modulating Treg populations to induce islet-specific tolerance. We also hypothesize that aAPC-mediated presentation of an autoreactive insulin peptide in the context of these additional tolerogenic cues will mediate enhanced aAPC-based Treg induction and expansion in vivo in a mouse diabetes model.
In Specific Aim 1, we will evaluate the capabilities of aAPC with encapsulated and surface- conjugated signal 1, 2 and 3 molecules to induce Tregs.
In Specific Aim 2, we will investigate the capacity of aAPC with a surface-conjugated IL-2 immunocytokine to expand Treg populations.
In Specific Aim 3, we will analyze the functionality of aAPC-modulated Tregs.
In Specific Aim 4, we will determine the potential of aAPCs to induce tolerance in a mouse model of spontaneous diabetes. The contributions of the present proposal are significant because it will be the first study to utilize two distinct aAPCs to treat T1D through 1) induction and 2) expansion of Treg populations, allow for direct comparison of the roles of each process in preventing T1D in mice, and investigate a potential synergy between Treg induction and expansion for diabetes treatment. If successful, this work will have a substantial positive impact on improving treatments for T1D patients.
The research described in this proposal aims to develop a new cell-mimicking particle-based platform to establish tolerance toward insulin-producing beta islet cells to treat Type 1 Diabetes. These artificial cells can reeducate the immune system to correctly recognize beta islet cells by stimulating a population of T cells with regulatory functions to suppress disease-causing autoreactive T cells while leaving the rest of the immune system intact. This technology has the potential to treat individuals with Type 1 Diabetes by halting T cell-mediated beta islet destruction and provide insight on effective strategies for diabetes-specific tolerance induction.
