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
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.