Models to study the synergy between autoimmunity and metabolism in T1D

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.

Grant Number: 5UG3DK142192-02
NIH Institute/Center: NIH
Principal Investigator: Michael Brehm