THE ROLE OF FAS LIGAND IN THE DEVELOPMENT OF INSULITIS IN NONOBESE DIABETIC MICE

The role of Fas ligand-induced lymphocyte apoptosis in the development of insulitis was studied in nonobese diabetic (NOD) mice. Fas ligand with a molecular weight of 45 kD appeared in the pancreas of NOD mice during the onset of insulitis as demonstrated by western blot analysis . In situ DNA end-labeling (ISEL) of the pancreases of NOD mice demons trated positive cells in the islets of Langerhans, with an age-depende nt increase in the density and frequency of animals with islets contai ning ISEL-positive cells. In the pancreatic islets of BALB/c mice, no ISEL-positive cells were observed in any of the age groups studied. In ultrastructural analysis degenerating cells with condensed or fragmen ted nuclei and plasma membranes detached from neighboring cells were o bserved both in and around the islets. In some cases, these cells were being phagocytosed by the neighboring islet cells. Degenerating cells with characteristics of lymphocytes were seen in contact with healthy lymphocytes around the islets. Neutralizing Fas ligand antibodies aff ected H-3-thymidine incorporation of CD3+CD28+ pancreatic lymphocytes from 12- to 30-week-old NOD mice in one of three cultures. There was n o difference in the effect of neutralizing Fas ligand antibodies betwe en pancreatic and blood lymphocytes. The present results on an increas e in density of apoptotic cells in pancreatic islets of NOD mice simul taneously with the onset of insulitis and appearance of Fas ligand sug gest that the pancreas infiltrating lymphocytes may be destroyed by Fa s ligand-induced apoptosis.