Linomide inhibits insulitis and modulates cytokine production in pancreatic islets in the nonobese diabetic mouse.
Linomide is an immunomodulator which has been shown to potently inhibit autoimmunity in several animal models for human autoimmune diseases, including type I diabetes in the nonobese diabetic (NOD) mouse. In this study, we investigate the basis for Linomide's protective effects in the NOD mouse by immunohistochemical and RT-PCR analysis of the phenotype and cytokine expression by cells infiltrating the islets of Langerhans in the pancreas. Linomide treatment was found to reduce the infiltration of T cells, B cells, dendritic cells (DC) and MHC class II(+) cells into the islets, but did not reduce macrophage (MPhi) infiltration. This was seen following Linomide treatment at 3-5, 4-8 and 14-24 weeks of age and thus appears to be independent of the stage of the autoreactive process and the extent of insulitis. The reduced insulitis may be due to reduced expression of adhesion molecules since decreased numbers of islet-associated blood vessels expressing CD106 and MAdCAM-1 were detected following Linomide treatment. Furthermore, short term Linomide treatment (3 or 7 days), which did not alter the number of infiltrating cells, was found to inhibit the production of TNF-alpha which is known to induce the expression of CD106 and MAdCAM-1. These results suggest that the reduced insulitis observed in Linomide-treated animals is secondary to a functional modulation of infiltrating cells.
Dahlén
Eva
E
Active Biotech Research AB, Box 724, SE-220 07 Lund, Sweden.
Dawe
Kim
K
Ohlsson
Lennart
L
Hall
Håkan
H
Hedse
Karin
K
Annersten
Karin
K
Aström
Mikael
M
Gross
David J
DJ
Hedlund
Gunnar
G
D000375:Aging; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D006912:Hydroxyquinolines; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; C045282:roquinimex