Syngeneic T cell transfer of diabetes into NOD newborn mice: in situ studies of the autoimmune steps leading to insulin-producing cell destruction.
To overcome the limitations of in situ studies during the chronic spontaneous autoimmune process leading to insulin cell destruction and diabetes in non-obese diabetic (NOD) mice, we have developed a model of acute transfer of diabetes into healthy syngeneic newborns. The injection of 20 x 10(6) T cells from adult diabetic mice produced synchronous insulitis within 3 weeks and diabetes within 4-5 weeks in young recipients, at a time when non-injected control mice do not even exhibit histological changes in their pancreases. Sequential studies of pancreases from T cell-transferred mice showed that lymphoid infiltration was preceded by a strong tissue expression of Ia antigen which was restricted to the vessel-associated cells limiting the islet of Langerhans, and which might play a role in the recruitment of circulating T cells inside the islets. Acute destruction of most of the insulin-producing cells, leading to diabetes, could take place within a few days after insulitis had begun. A majority of the inflammatory cells were T lymphocytes, approximately 30% of which expressed interleukin 2 receptors. L3T4+ T cells largely predominated at the early phase of islet invasion whereas the proportion of Ly-2+ T cells substantially increased later when beta cell destruction occurred. In contrast, only a minority of B cells and macrophages participated to the inflammatory process. These data are in keeping with previous demonstrations that both T cell subsets contribute to the autoimmune disease. Furthermore, they suggest that beta cell injury is mediated through a cytotoxic process, which requires the sequential involvement of L3T4+ (helper) and Ly-2+ (cytotoxic) T cells.
Bedossa
P
P
INSERM U 25, CNRS UA 122, Hôpital Necker, Paris, France.
Bendelac
A
A
Bach
J F
JF
Carnaud
C
C
D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007116:Immunization, Passive; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D007328:Insulin