Project Abstracts - CMAD

George Daley, PhD, Harvard Medical School
Accali Fu, PhD, University of Massachusetts Medical School
David Harlan, MD, University of Massachusetts Medical School
David Marshall, PhD, University of Massachusetts Medical School
Leonard Shultz, PhD, The Jackson Laboratory
Peng Yi, PhD, Joslin Diabetes Center

Start Date: December 15, 2025

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Abstract

The development of human type 1 diabetes (T1D) involves complex interactions between pancreatic β-cells and the immune system that are still not fully understood. We propose to study the dynamic interactions between human immune systems from individuals with T1D and autologous human islets derived from donor iPSC (SC- islets) using translational humanized mouse models and in vitro metabolic profiling platforms. This proposal is in response to RFA-DK-23-004 for Human Islet Research Network – Consortium on Modeling Autoimmune Diabetes (HIRN-CMAD) (UG3/UH3) that has a primary goal to support “the development of in vitro and in vivo models of T1D to enable studies of human T1D pathophysiology and to serve as platforms for preclinical assessments of new T1D interventions.” Our long-term goal is to generate humanized mice to model T1D using human SC-islets differentiated from T1D iPSC and co-engrafting autologous immune systems from primary PBMC or SC-derived hematopoietic cells. The proposed models would enable the direct study of interactions between human immune cells and autologous SC-islets for both effector mechanisms and the exchange of metabolites regulating inflammation. A central feature for our application is the cutting-edge humanized mouse models developed by Dr. Leonard Shultz at The Jackson Laboratory. Recent advancement in the NOD-scid IL2rgnull (NSG) strains by the Shultz lab have created new models that 1) support the engraftment of human B cells, NK cells and T cells following PBMC injection, 2) bear the W41 mutation in the mouse kit gene and are more permissive to HSC engraftment in the absence of irradiation preconditioning and 3) enable the generation of peripheral lymph nodes, including pancreatic lymph nodes, after engraftment with umbilical cord blood (UCB)- CD34+ HSC when treated with an AAV vector expressing mouse thymic stromal lymphopoietin (TSLP). We have assembled a team of investigators from 4 institutions, UMCMS, Harvard, Joslin and The Jackson Laboratory to test our overall hypothesis that our proposed studies of autologous human SC-islets and immune cells transplanted into novel humanized mouse models accompanied by in vitro metabolic profiling will increase the understanding of dynamic cellular and metabolic interactions that drive human T1D. We will test this hypothesis in 3 Aims; Aim 1. Interrogate interactions between autologous immune systems and SC-islets in vivo, Aim 2. Identify and characterize metabolic pathways influencing SC-islet survival during inflammation, and Aim 3. Develop SC-HSC from iPSC and explore the role of pancreatic lymph nodes in T1D. The proposed studies will provide a mechanistic understanding of the factors that contribute to the induction of T1D in humans and will provide critical benchmarks for the effective design of therapeutic strategies for T1D and for the identification of specific patient populations that will respond optimally to treatment modalities.