title: Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice.
abstract: 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 approximately 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, approximately 20% of pancreas-infiltrating CD4+ T cells produced IFN-gamma, 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.
authors.affiliation: Roche Milano Ricerche, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Trembleau
authors.forename: G
authors.initials: G
authors.lastname: Penna
authors.forename: S
authors.initials: S
authors.lastname: Gregori
authors.forename: H D
authors.initials: HD
authors.lastname: Chapman
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
authors.forename: J
authors.initials: J
authors.lastname: Magram
authors.forename: L
authors.initials: L
authors.lastname: Adorini
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D018791:CD4 Lymphocyte Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D019007:P-Selectin / Q000378:metabolism; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019007:P-Selectin; D018664:Interleukin-12; D007371:Interferon-gamma; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8