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

Abstract

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 42weeks (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. [Diabetologia (1994[Diabetologia ( ) 37: 1195[Diabetologia ( -1201

Mycophenolate Mofetil, Azathioprine and Cyclophosphamide Enhanced Efficacy Combined with Cyclosporine in Rat Cardiac Transplantation

“…It was also shown to aggravate graft versus host disease after experimental small bowel transplantation [30]. However, Lin is not to be regarded as an immunostimulator only, as in models of autoimmune disease the drug depresses the immune reaction and thereby normalizes the function of the system [31][32][33][34].…”

Linomide Enhances Apoptosis in CD4+CD8+ Thymocytes

“…Modulation of T cell development in the thymus will inevitably have consequences on the development of the T cell repertoire. The therapeutic effect of Linomide in several models of autoimmune disease [8][9][10], together with its impact on thymus [11], warranted further investigation of the Linomide effect on T cell development. The course of the thymocyte cell number reduction in normal mice receiving Linomide consisted of an initial profound decrease in the CD4 þ CD8 þ subset, which was shown to be due to enhanced induction of apoptosis in these cells.…”

“…Apoptosis also occurs following exposure of thymocytes to glucocorticoids (GC) such as dexamethasone, which lead to the rapid atrophy of the thymus [4]. Linomide, quinoline-3-carboxamide, (roquinimex, LS2616) has been shown to modulate a number of immune functions [5][6][7], foremost, Linomide has been shown to have a potent ameliorative effect in a variety of autoimmune disease models such as systemic lupus erythematosus (SLE)-like syndrome [8], experimental autoimmune encephalomyelitis [9] and insulin dependent diabetes mellitus [10]. In the SLE model, Linomide prolongs survival and delays organ pathology of MRL lpr/1pr mice.…”

Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers

“…The plasma samples were thawed at room temperature and centrifuged at 800× g for 5 min. 3 H-labelled roquinimex was added to 1 mL of plasma at a concentration of 2 mM. After equilibration at 37°C for 30 min, the pH of the sample was adjusted to 7.40 by gassing with 50% CO 2 , 50% O 2 .…”