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

Citation
S. Miyaguchi et al., Human LT-alpha-mediated resistance to autoimmune diabetes is induced in NOD, but not NOD-scid, mice and abrogated by IL-12, CLIN IMMUNO, 98(1), 2001, pp. 119-124
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Clinical Immunolgy & Infectious Disease",Immunology
Journal title
CLINICAL IMMUNOLOGY
ISSN journal
1521-6616 → ACNP
Volume
98
Issue
1
Year of publication
2001
Pages
119 - 124
Database
ISI
SICI code
1521-6616(200101)98:1<119:HLRTAD>2.0.ZU;2-7
Abstract
Systemic administration of human lymphotoxin-alpha (hLT-alpha) made NOD mic e resistant not only to spontaneous autoimmune type 1 diabetes mellitus but also to cyclophosphamide (CY)-induced diabetes and diabetes transfer by di abetic NOD spleen cells (triple resistance). In this study we analyzed the mechanisms of hLT-alpha -induced resistance, focusing on (1) hLT-alpha -ind uced resistance in the pancreatic beta cell, (2) CY-resistant suppressor ce lls, (3) suppression of induction or function of effector cells for beta ce ll 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 c ytotoxicity. Next NOD-scid mice were pretreated with hLT-alpha and then tra nsferred with diabetic NOD spleen. All the recipients developed diabetes. T hese results excluded the first possibility. The second possibility was als o excluded by a cotransfer experiment, in which diabetic NOD spleen cells w ere cotransferred to NOD-scid mice with nontreated or hLT-alpha -treated no ndiabetic NOD spleens. There was no significant difference in diabetes inci dence between the two groups. To observe the third possibility, spleen cell s of hLT-alpha -treated triple-resistant NOD mice were transferred to NOD-s cid mice. Diabetes developed in the recipients, although the onset of diabe tes 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 ce ll destruction. This resistance was induced in NOD, but not in NOD-scid, mi ce, indicating that lymphocytes were obligatory for the resistance. However , it was not mediated by transferable suppressor cells. Because effector ce lls were present in hLT-alpha -treated NOD spleen and the resistance was ab rogated by IL-12 treatment, it is speculated that hLT-alpha treatment may h ave changed a local cytokine balance protective from beta cell destruction. (C) 2000 Academic Press.