Cellular and molecular changes accompanying the progression from insulitis to diabetes

Eur J Immunol. 1999 Jan;29(1):245-55. doi: 10.1002/(SICI)1521-4141(199901)29:01<245::AID-IMMU245>3.0.CO;2-O.


Insulin-dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages - insulitis and diabetes - and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non-universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100% of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL-18, IL-12 and TNF-alpha were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL-1 -beta, IL-6 and IFN-gamma, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact-mediated mechanisms of beta cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens
  • Cyclophosphamide / toxicity
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Humans
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Microscopy, Electron
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / genetics


  • Autoantigens
  • Cytokines
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Cyclophosphamide