Recombinant Lactococcus lactis Carrying IL-4 and IL-10 Coding Vectors Protects against Type 1 Diabetes in NOD Mice and Attenuates Insulitis in the STZ-Induced Model

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that culminates in beta cell destruction in the pancreas and, subsequently, deficiency in insulin production. Cytokines play a crucial role in the development of diabetes, orchestrating the recruitment and action of immune cells, to not only destroy insulin-producing cells but also preserve them. Therefore, the aim of this study was to investigate the effect of orally administered Lactococcus lactis MG1363 FnBPA+ strains carrying plasmids encoding IL-4 and IL-10 in the streptozotocin- (STZ-) induced diabetes model and in nonobese diabetic (NOD) mice. The STZ-induced mice that were treated with combined bacterial strains carrying plasmids encoding IL-4 and IL-10 showed lower incidence of diabetes and more preserved pancreatic islets than the mice that received the individual bacterial strains. Combined administration of L. lactis MG1363 FnBPA+ (pValac::dts::IL-4) and L. lactis MG1363 FnBPA+ (pValac::IL-10) resulted in protection against diabetes in NOD mice. It was shown that the combined treatment with recombinant bacterial by oral route prevented hyperglycemia and reduced the pancreatic islets-destruction in NOD mice. In addition, increased levels of IL-4 and IL-10 in serum and pancreatic tissue revealed a systemic effect of the treatment and also favored an anti-inflammatory microenvironment. Reduced concentrations of IL-12 in pancreas were essential to the regulation of inflammation, resulting in no incidence of diabetes in treated NOD mice. Normal levels of intestinal sIgA after long-term treatment with the L. lactis strains carrying plasmids encoding IL-4 and IL-10 indicate the development of oral tolerance and corroborate the use of this potent tool of mucosal delivery. For the first time, L. lactis MG1363 FnBPA+ strains carrying eukaryotic expression vectors encoding IL-4 and IL-10 are tested in STZ-induced and NOD mouse models. Therefore, our study demonstrates this innovative strategy provides immunomodulatory potential for further investigations in T1D and other autoimmune diseases.

The engineered probiotics for the treatment of chronic diseases: A systematic review

“…As mentioned before, preparing exogenous source of anti‐inflammatory cytokines and suppression of immune response versus HSP‐65 can improve disease activity in auto‐immune diseases. The experimental studies have been conducted on diabetes and CVD and also reported similar results (Duan et al, 2015; Preisser et al, 2021; Takiishi et al, 2012). This means that CVD and diabetes are diseases with immunological roots.…”

Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia

“…In many previous studies, the roles of the Th 1 and Th 2 cytokines were well investigated under many neurodegenerative and autoimmune diseases. Th 1 cytokines, such as TNF-α and IFN-γ, are known to lead the progression of autoimmune diseases such as type 1 diabetes and multiple sclerosis (MS) [26][27][28], while IL-4, IL-10, and IL-13 refer to Th 2 cytokines and inhibit the pro-inflammatory response and reduce damage [29][30][31]. Furthermore, IL-37 plays an anti-inflammatory role and suppresses the pathogenesis of MS [32,33].…”

Enhancing effect of streptozotocin-induced insulin deficit on antitumor innate immune defense in rats

“…It seems logical that type-1 natural immune defense suppresses the type-2 system which serves to protect insulin production and effect. This insulin-protective effect of type-2 cytokines (such as IL-4 and IL-10) in STZ-induced mice diabetes model was also established [42].…”