Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse

Abstract

Quinoline-3-carboxamides (Q compounds) are immunomodulatory compounds that have shown efficacy both in autoimmune disease and cancer. We have in here investigated the impact of one such compound, paquinimod, on the development of diabetes in the NOD mouse model for type I diabetes (T1D). In cohorts of NOD mice treated with paquinimod between weeks 10 to 20 of age and followed up until 40 weeks of age, we observed dose-dependent reduction in incidence of disease as well as delayed onset of disease. Further, in contrast to untreated controls, the majority of NOD mice treated from 15 weeks of age did not develop diabetes at 30 weeks of age. Importantly, these mice displayed significantly less insulitis, which correlated with selectively reduced number of splenic macrophages and splenic Ly6Chi inflammatory monocytes at end point as compared to untreated controls. Collectively, these results demonstrate that paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse. We propose that the effect of paquinimod on disease progression may be related to the reduced number of these myeloid cell populations. Our finding also indicates that this compound could be a candidate for clinical development towards diabetes therapy in humans.

Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes a CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity

“…Quinoline-3-carboxamide derivatives such as laquinimod, tasquinimod, or pasquinimod have shown immunomodulatory, anti-tumor, and anti-angiogenic effects in pre-clinical animal models [24–26]. So far, the modulation of myeloid cells was primarily held responsible for their immunomodulatory and anti-tumor effects [27–31]. Here, we provide evidence that the aryl hydrocarbon receptor-dependent activation of NK cells is relevant for the efficacy of laquinimod to suppress melanoma cell metastases and CNS autoimmunity.…”

Butyrate induced Tregs are capable of migration from the GALT to the pancreas to restore immunological tolerance during type-1 diabetes

“…The degree of insulitis was scored according to the following criteria: Score 0, no insulitis; Score 1, peri-insulitis; Score 2, mild insulitis (less than 25% infiltration); Score 2, severe insulitis (25% to 75% infiltration); Score 3, destructive insulitis (more than 75% infiltration) ( Supplementary Fig S1). The insulitis index was calculated according to the formula; Insulitis index = (0 × n 0 ) + (1 × n 1 ) + (2 × n 2 ) + (3 × n 3 ) + (4 × n4) / 4 (n 0 + n 1 + n 2 + n 3 + n 4 ), where n 0 -n 4 denotes the number of islets of scores from 0 to 4 40 . The histomorphometric analysis of insulin was performed by indirect immunohistochemistry.…”

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

“…In studies on pancreata from human subjects with T1D, macrophages have been found to be an important part of the islet infiltrate, thereby underlining their role in the immune events, which precipitate autoimmune diabetes ( 11 , 70 ). Macrophage depletion and functional inhibition have been shown to reduce the development of autoimmune diabetes in rodent models ( 71 – 73 ). Similarly, NOD mice deficient in CD103+ DCs were found to have a reduced islet infiltration of autoreactive T cells and a corresponding reduction in diabetes incidence ( 74 ).…”