Human LT-α-Mediated Resistance to Autoimmune Diabetes Is Induced in NOD, but Not NOD-Scid, Mice and Abrogated by IL-12

Systemic administration of human lymphotoxin-α (hLT-α) made NOD mice resistant not only to spontaneous autoimmune type 1 diabetes mellitus but also to cyclophosphamide (CY)-induced diabetes and diabetes transfer by diabetic NOD spleen cells (triple resistance). In this study we analyzed the mechanisms of hLT-α-induced resistance, focusing on (1) hLT-α-induced resistance in the pancreatic β cell, (2) CY-resistant suppressor cells, (3) suppression of induction or function of effector cells for β cell destruction, or (4) others. To examine the first possibility in vitro, a NOD-derived β cell line (MIN6N) was pretreated with hLT-α and then mixed with diabetic NOD spleen cells and MIN6N cell viability was measured. Treatment with hLT-α did not protect MIN6N cells but rather enhanced cytotoxicity. Next NOD-scid mice were pretreated with hLT-α and then transferred with diabetic NOD spleen. All the recipients developed diabetes. These results excluded the first possibility. The second possibility was also excluded by a cotransfer experiment, in which diabetic NOD spleen cells were cotransferred to NOD-scid mice with nontreated or hLT-α-treated nondiabetic NOD spleens. There was no significant difference in diabetes incidence between the two groups. To observe the third possibility, spleen cells of hLT-α-treated triple-resistant NOD mice were transferred to NOD-scid mice. Diabetes developed in the recipients, although the onset of diabetes was slightly delayed. Finally, hLT-α-treated triple-resistant NOD mice developed diabetes 1 week after daily IL-12 treatment. In summary, hLT-α administration made NOD mice resistant to effector cells for β cell destruction. This resistance was induced in NOD, but not in NOD-scid, mice, indicating that lymphocytes were obligatory for the resistance. However, it was not mediated by transferable suppressor cells. Because effector cells were present in hLT-α-treated NOD spleen and the resistance was abrogated by IL-12 treatment, it is speculated that hLT-α treatment may have changed a local cytokine balance protective from β cell destruction.