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ADA Mentor-Based Postdoctoral Fellowship Award

Nichole M. Danzl, PhD

Cell intrinisc immunopathology of type 1 diabetes in a humanized mouse model

In Type 1 diabetes (T1DM) multiple genetic determinants encoding HLA and immunomodulatory molecules create an environment predisposed to immune cell-mediated attack of pancreatic beta cells.  Faulty induction and maintenance of self-tolerance is critical to disease evolution, as shown by observed abnormalities in immunoregulatory populations and autoimmune pathogenesis of T1DM in patients and the NOD mouse model.  Since these observations are made after T1DM onset, the direct relevance of these abnormalities to disease initiation and progression is unclear.  It is clear that T1DM susceptibility is transferred in hematopoietic stem cells (HSCs) in both mouse and man, suggesting that intrinsic defects in HSCs contribute to development of autoimmunity.

We hypothesize that the genetic predisposition to T1DM is associated with hematopoietic-intrinsic abnormalities affecting induction and maintenance of self-tolerance.