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Dale L. Greiner, PhD: Type 1 Diabetes Research in Humanized Mouse Models

Studying Human Diabetes in Humanized Mice

Understanding human immune responses, both how to turn them off for the treatment of type 1 diabetes and autoimmunity and conversely, to use the same pathways to turn the immune response on for the treatment of cancer. For these studies, we use animal models of human immune responses for investigating these approaches to downregulate as well as activate the human immune system.

Type 1 Diabetes Etiology and Pathogenesis

Understanding the etiology and pathogenesis of autoimmune type 1 diabetes mellitus (T1D).  Our approach focuses on two main areas: 

  • Understanding the pathogenesis of T1D so as to formulate means to prevent or reverse the disease.
  • The cure of those who are diabetic by induction of transplantation tolerance to islets of Langerhans.

More than 25 years ago, we and others cured type 1 diabetes in spontaneously diabetic mouse and rat models of T1D, but these accomplishments have not yet been successfully translated to humans. 

We believe there are two major obstacles that prevent the achievement of these goals in humans:

  • Lack of understanding of the biology of how human insulin-secreting beta cells die during the development of T1D.
  • Lack of understanding of how a human immune system mediates the destruction of human beta cells in vivo.

Our Unique Humanized Mouse Model

The Greiner Laboratory at UMass Diabetes Center of Excellence, in collaboration with Dr. Leonard Shultz at The Jackson Laboratory and Dr. Michael Brehm at UMass Chan Medical School, have developed unique strains of mice, allowing us to understand and dissect mechanisms important in human immune response that are difficult to study directly in humans. 

Our animal models are helping us to understand:

  • How human beta cells resist killing by a human immune system in vivo
  • How human beta cells replicate and regenerate in vivo
  • How human islet-reactive cells develop in a human diabetes-susceptible immune system
  • How a human immune system targets and kills beta cells in vivo

Through multiple collaborations, the Greiner Lab is also using our unique mouse model to study human regenerative medicine, immunity, human-specific infectious agents and cancer. These studies have the potential to guide human clinical trials by determining the mechanisms by which therapeutic drugs, such as those based on targeting immune “checkpoints” that control how an immune system is turned off and on, will act directly on human immune systems, islets, and cancers in vivo, facilitating the direct translation of these agents into the clinic.