Prevention of diabetes mellitus in non-obese diabetic mice by Linomide,a novel immunomodulating drug

Summary Oral administration of the synthetic immunomodulating drug quinoline-3-carboxamide (Linomide) in the drinking water to 5-week-old female non-obese diabetic (NOD) mice resulted in complete protection from insulitis and maintenance of normal glucose tolerance for over 40 weeks (impaired glucose tolerance: treated n=2 of 18; control n=17 of 18, p<0.0001). Delayed administration of the drug at 16 weeks resulted in slowing of the progression to diabetes when assessed at 42 weeks (treated with diabetes n=7 of 25; control with diabetes 25 of 43, p<0.0234). No gross changes of immune system cell phenotype or function were observed in the Linomide-treated group. Adoptive transfer of spleen and lymph node cells from treated female NOD mice into sub-lethally irradiated male recipients failed to transfer diabetes, whereas a similar transfer of cells obtained from untreated age-matched controls resulted in diabetes in all secondary recipients (diabetes in control group n=12 of 13; in Linomide group n=0 of 11, p<0.0001). Linomide pretreatment of the secondary recipients also inhibited the transfer of diabetes (diabetes in pretreated group n=2 of 9, control group n=12 of 13, p<0.015), as did adoptive co-transfer of cell mixtures obtained from treated female NOD mice, free of diabetes, and from diabetic NOD female mice (diabetes in Linomide group n=4 of 9; in control group 7 of 7, p<0.0337). Our data indicate that Linomide-treated NOD mice generate immune cells with the capacity to downregulate responses to beta-cell antigens, apparently through immunoregulation rather then antigen non-specific immunosuppression. Based on our findings and considering the lack of severe side effects of orally administered Linomide in man, this new compound should be considered as a potential drug for treatment of insulin-dependent diabetes mellitus.Abbreviations IDDM Insulin-dependent diabetes mellitus - NK natural killer - IL interleukin - NOD non-obese diabetic - IPGTT intraperitoneal glucose tolerance test - FITC fluorescein-5-isothiocyanate - DTAF 5(4,6 dichlorotriazinyl) aminofluorescein - FACS fluorescein activated cell sorting - PHA phythaemagglutinin - Con A concanavalin A - SEA staphylococcal extract A - SEB staphylococcal extract B - SRBC sheep erythrocytes - HBSS Hanks buffered salt solution - LPS lipopolysaccharide - MLR mixed lymphocyte reaction - DTH delayed-type, hypersensitivity - BCG Bacillus Calmette Guerrin - APC antigen presenting cell - TNF- tumor necrosis factor-