A Humanized Mouse Model of Autoimmune Insulitis
- Ashley A. Viehmann Milam1,2,
- Stephen E. Maher1,
- Joanna A. Gibson3,
- Jasmin Lebastchi1,4,
- Li Wen5,
- Nancy H. Ruddle1,6,
- Kevan C. Herold1,4 and
- Alfred L.M. Bothwell1⇑
- 1Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
- 2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO.
- 3Department of Pathology, Yale University School of Medicine, New Haven, CT.
- 4Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
- 5Section of Endocrinology, Yale University School of Medicine.
- 6School of Public Health, Yale University, New Haven, CT.
- Corresponding Author: Dr. Alfred Bothwell E-mail:
Many mechanisms of and treatments for Type 1 diabetes studied in the NOD mouse model have failed to replicate in human disease. Thus, the field of diabetes research remains hindered by lack of an in vivo system in which to study the development and onset of autoimmune diabetes. To this end, we have characterized a system using human CD4+ T cells pulsed with autoantigen-derived peptides. Six weeks after injection of as few as 0.5x106 antigen-pulsed cells into the NOD-Scid Il2rg-/- mouse expressing the human HLA-DR4 transgene, infiltration of mouse islets by human T cells was seen. While islet infiltration occurred with both healthy and diabetic donor antigen-pulsed CD4+ T cells, diabetic donor injections yielded significantly greater levels of insulitis. Additionally, significantly reduced insulin staining was observed in mice injected with CD4+ T cell lines from diabetic donors. Increased levels of demethylated β cell-derived DNA in the bloodstream accompanied this loss of insulin staining. Together, these data show that injection of small numbers of autoantigen-reactive CD4+ T cells can cause a targeted, destructive infiltration of pancreatic β cells. This model may be valuable for understanding mechanisms of induction of human diabetes.
- Received July 23, 2013.
- Accepted January 8, 2014.
- © 2014 by the American Diabetes Association.
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