Human Islet Research Network

Project Abstracts - OPP

Islet-reactive TCR clones in humanized mice generated with type 1 diabetes patient vs. healthy control hematopoietic stem cells

Contact PI: Megan Sykes, MD

Type 1 diabetes (T1D) is an autoimmune disease in which immune cells attack the cells responsible for insulin
production, pancreatic beta cells. The study of autoimmune diseases such as T1D has, until recently, been
limited by the insufficiency of animal models and by the restriction of human patient samples to peripheral
blood, which may not reflect immunity in the end organs. Moreover, patient populations are heterogeneous
with respect to the duration of disease, treatments, comorbidities, genetic background and environmental
exposures, making it difficult to identify pathophysiologic mechanisms. We have developed a “Personalized
Immune” (PI) humanized mouse model that overcomes these limitations by allowing synchronized de novo
development, in immunodeficient mice, of functional human immune systems from hematopoietic stem cells
(HSCs) of T1D patients and healthy controls (HCs). In addition, fetal thymus tissue that shares essential
immune system genes with the patient (HLA genes) is also transplanted to these mice to support generation of
new human T cells. Mice are thereby reconstituted with human immune cells. Since genetic drivers of immune
dysregulation are delivered from the T1D patient to the mouse through donor HSCs, the mouse has the genes
in its human cells to drive disease development. This model allows us to study the factors that are involved in
development of T1D. It is not known whether there is a defect in education of T cells in the thymus, where they
normally learn not to attack self-molecules, including those expressed in pancreatic beta cells, or if other
underlying genetic factors allow expansion of autoreactive T cells that can attack pancreatic islets after they
leave the thymus. To address this question, we will use the T1D vs HC PI mouse model and identify isletreactive
T cells within the thymus and in the periphery (spleen and lymph node), by sequencing their receptors
and comparing them to our bank of known islet-reactive T cell receptors obtained from T1D patients. This
approach provides a new window into events inside and outside of the thymus involved in T1D pathogenesis,
and can point to us where we should concentrate our efforts to find the final cure.

Opportunity Pool Project Sponsored by CMAI.
Awarded: 2017