Heparanase prevents the development of type 1 diabetes in non‐obese diabetic mice by regulating T‐cell activation and cytokines production

Abstract

We suggest that heparanase induces a shift from a Th1- to Th2-phenotype, resulting in inhibition of diabetes in NOD mice and possibly other autoimmune disorders.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…Because these molecules regulate HA binding to CD44, they may affect the phenotypes associated with HA (32). Other components of the ECM are also reported to contribute to the development and progression of insulitis, either through HA-dependent or -independent mechanisms (6,(33)(34)(35)(36)(37). Taken together with our recent work on HA in human T1D (6), the progression to autoimmune diabetes is associated with profound changes in the ECM architecture.…”

Preimplantation factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice

“…In this model in females by 12 weeks start to develop diabetes and by 18-20 weeks 90% of them become diabetic. In contrast, male NOD mice develop spontaneously DM only in 10% [11,12]. To address the principal etiologies that lead to TIDM development, we examined sPIF's efficacy in two relevant NOD models, adoptive-transfer (rapidly immune-induced) and in spontaneously developing mice.…”

“…Since PIF has immune modulatory properties; herein we investigate the synthetic version of PIF (sPIF) effectiveness in preventing TIDM by preserving islet function using the NOD mouse model which is frequently used to test novel therapies against TIDM [8][9][10][11][12][13]. In this model in females by 12 weeks start to develop diabetes and by 18-20 weeks 90% of them become diabetic.…”

“…In addition, immune therapies by using antibodies (anti-CD3 and antithymocyte globulin) to block the autoimmune cascade [8,9] combined with agents that repair or regenerate beta cells (e.g., glulisine, glucagon-like-peptide-1 (GLP-1), extendin-4, and Dia-Pep277) were tested. Also, more recently nonmyeloablative allogenic bone marrow transplantation and heparanase were tested with variable success [8][9][10][11][12][13]. In TIDM total islet destruction does not frequently occur.…”

Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation

“…42 Furthermore, a recent report has shown that heparanase treatment of mice is protective against GVHD in the setting of allo-HSCT. 43 Heparanase therapy also has been shown to decrease the severity of disease in mouse models of experimental autoimmune encephalitis 44 and type I diabetes mellitus, 45 both T cell-mediated diseases. Taken together, these observations suggest a possible mechanism whereby tissue invading alloreactive T cells degrade the extracellular matrix and generate soluble HS at the onset of GVHD.…”