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*
Roche Milano Ricerche, Milano, Italy;
The Jackson Laboratory, Bar Harbor, ME 04609; and
Department of Biotechnology, Hoffmann-La Roche, Nutley, NJ 07110
IL-12 and IL-12 antagonist administration to nonobese diabetic
(NOD) mice accelerates and prevents insulin-dependent diabetes mellitus
(IDDM), respectively. To further define the role of endogenous IL-12 in
the development of diabetogenic Th1 cells, IL-12-deficient NOD mice
were generated and analyzed. Th1 responses to exogenous Ags were
reduced by 
80% in draining lymph nodes of these mice, and addition
of IL-12, but not IL-18, restored Th1 development in vitro, indicating
a nonredundant role of IL-12. Moreover, spontaneous Th1 responses to a
self Ag, the tyrosine phosphatase-like IA-2, were undetectable in
lymphoid organs from IL-12-deficient, in contrast to wild-type, NOD
mice. Nevertheless, wild-type and IL-12-deficient NOD mice developed
similar insulitis and IDDM. Both in wild-type and IL-12-deficient NOD
mice, 20% of pancreas-infiltrating CD4+ T cells
produced IFN-
, whereas very few produced IL-10 or IL-4, indicating
that IDDM was associated with a type 1 T cell infiltrate in the target
organ. T cell recruitment in the pancreas seemed favored in
IL-12-deficient NOD mice, as revealed by increased P-selectin ligand
expression on pancreas-infiltrating T cells, and this could, at least
in part, compensate for the defective Th1 cell pool recruitable from
peripheral lymphoid organs. Residual Th1 cells could also accumulate in
the pancreas of IL-12-deficient NOD mice because Th2 cells were not
induced, in contrast to wild-type NOD mice treated with an IL-12
antagonist. Thus, a regulatory pathway seems necessary to counteract
the pathogenic Th1 cells that develop in the absence of IL-12 in a
spontaneous chronic progressive autoimmune disease under polygenic
control, such as IDDM.
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