Human LT-alpha-mediated resistance to autoimmune diabetes is induced in NOD, but not NOD-scid, mice and abrogated by IL-12.

Abstract

Systemic administration of human lymphotoxin-alpha (hLT-alpha) 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-alpha-induced resistance, focusing on (1) hLT-alpha-induced resistance in the pancreatic beta cell, (2) CY-resistant suppressor cells, (3) suppression of induction or function of effector cells for beta cell destruction, or (4) others. To examine the first possibility in vitro, a NOD-derived beta cell line (MIN6N) was pretreated with hLT-alpha and then mixed with diabetic NOD spleen cells and MIN6N cell viability was measured. Treatment with hLT-alpha did not protect MIN6N cells but rather enhanced cytotoxicity. Next NOD-scid mice were pretreated with hLT-alpha 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-alpha-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-alpha-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-alpha-treated triple-resistant NOD mice developed diabetes 1 week after daily IL-12 treatment. In summary, hLT-alpha administration made NOD mice resistant to effector cells for beta 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-alpha-treated NOD spleen and the resistance was abrogated by IL-12 treatment, it is speculated that hLT-alpha treatment may have changed a local cytokine balance protective from beta cell destruction.

• Authors: S Miyaguchi, J Satoh, K Takahashi, Y Sakata, T Nakazawa, J Miyazaki, T Toyota
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 98 Issue 1 Pg. 119-24 (Jan 2001) ISSN: 1521-6616 [Print] United States
• PMID: 11141334 (Publication Type: Journal Article)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Lymphotoxin-alpha
• Interleukin-12

Topics

• Animals
• Cytotoxicity, Immunologic
• Diabetes Mellitus, Type 1 (immunology, prevention & control)
• Disease Models, Animal
• Female
• Humans
• Immunity, Innate (drug effects)
• Interleukin-12 (therapeutic use)
• Lymphotoxin-alpha (pharmacology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Spleen (cytology)