# Engineered extracellular vesicles derived from mesenchymal stem cells for the treatment of type 1 diabetes > **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2024 · $567,641 ## Abstract Abstract Type 1 diabetes (T1D) is an autoimmune disease wherein a loss in immune tolerance leads to the initiation and progressive destruction of insulin-producing β cells. Numerous immune interventions have been reported to delay β-cell loss, but a few clinical trials have demonstrated safety and efficacy. Arguably, Fc receptor–nonbinding anti-CD3 monoclonal antibodies (anti-CD3 mAb) have been the most successful clinical immunotherapy for T1D, showing promising clinical outcomes in patients with new onset T1D as well as high- risk, nondiabetic relatives of T1D patients. However, a significant number of patients still did not respond positively to anti-CD3 therapy and the duration of response is limited. Hence, there is a critical need to develop novel therapeutic interventions to induce immune tolerance for the treatment of T1D. Programmed cell death protein 1 (PD-1): PD-Ligand 1 (PD-L1) axis plays important roles in immune tolerance. NOD mice lacking PD- L1 or PD-1 develop accelerated T1D and PD-1/PD-L1 expression is low in immune cells of both NOD mice and T1D patients. Genetically engineering approaches to overexpress PD-L1 or PD-1 in immune cells have shown to promote immune tolerance in T1D. However, there are still challenges in clinical applications of viral engineered cells such as toxicity, genotoxicity, low engraftment of gene-edited cells. PD-1/PD-L1 axis also plays a critical role in anti-CD3-mediated tolerance in T1D. Anti-CD3 therapy induces immune tolerance in overt T1D in TGFβ-dependent mechanisms, however CD3 antibody-induced remission of T1D in NOD mice is fully reversed by PD-1/PD-L1 blockade, suggesting that the PD-1/PD-L1 axis may also play a critical role in the response of T1D patients to anti-CD3 immunotherapy. Thus, combining anti-CD3 mAb with TGFb1/PD-L treatment may more synergistically restore immune tolerance in T1D; however, this has not yet been tested. Therefore, the overall goal of the proposed study is to develop a viral engineering- and cell-free strategy to deliver TGFβ1 and PD-L1 for inducing immune tolerance in T1D using extracellular vesicles (EVs) produced from mesenchymal stem cells (MSCs). Our central hypothesis that MSC-derived EVs (MSC-EVs) engineered to deliver TGFb1 and PD-L1 effectively induce immune tolerance in T1D and synergistically enhance anti-CD3- mediated tolerance in T1D. Aim 1 is to define the mechanisms by which EVs carrying TGFb1 and PD-L1 suppress auto-reactive T cells. Aim 2 is to demonstrate the therapeutic effect of the engineered EVs in prevention and reversal of T1D onset. Aim 3 is to examine the synergistic effect of the engineered EVs on anti- CD3-mediated tolerance. The proposed project will provide EV-based therapy to induce immune tolerance and help improve the efficacy and safety of anti-CD3 therapy in T1D. The significant preclinical data of the engineered EVs in prevention and reversal of new-onset T1D will facilitate the development of robust and ready- to-use MSC-EV the... ## Key facts - **NIH application ID:** 10882499 - **Project number:** 1R01DK136890-01A1 - **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR - **Principal Investigator:** Ryang Hwa Lee - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $567,641 - **Award type:** 1 - **Project period:** 2024-04-01 → 2029-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10882499 ## Citation > US National Institutes of Health, RePORTER application 10882499, Engineered extracellular vesicles derived from mesenchymal stem cells for the treatment of type 1 diabetes (1R01DK136890-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882499. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*