Tissue inhibitor of metalloproteinase-2 inhibits T-cell infiltration and preserves pancreatic beta-cell function in an in vitro type 1 diabetes mellitus model

Type 1 diabetes mellitus (T1DM) results from autoreactive T-cells that attack and destroy insulin producing pancreatic beta-cells. This knowledge has provided a framework for numerous efforts to prevent or mitigate T1DM at various stages of the disease. In this study, we utilized an organ culture model of type 1 diabetes to determine whether tissue inhibitors of metalloproteinases (TIMPs) could block T-cell migration into the pancreas and ultimately preserve beta-cell function. We measured T-cell repertoires, insulin secretion, and performed immunohistochemistry and confocal laser microscopy in order to evaluate the effect of TIMP-1, TIMP-2, and TIMP-3 on our in vitro T1DM organ culture model. TIMP-2 decreased T-cell transmigration and preserved insulin production in our T1DM organ culture model. Moreover, TIMP-2 inhibited transmigration of diabetogenic T-cells across an islet microvascular endothelial cell layer. Our findings suggest that TIMP-2 is effective at blocking infiltration of autoreactive T-cells into target pancreas tissue thereby preserving pancreatic beta-cell mass.