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.
Woods
Chris C
CC
Department of Microbiology & Immunology, University of Arizona College of Medicine, 1501 N. Campbell Avenue, Tuscon, 85724, USA.
Sundar
Krishnan
K
Tessler
Cynthia
C
Lebsack
Ty W
TW
Grainger
Lora
L
Nielsen
Alma
A
Bleich
David
D
DeLuca
Dominick
D
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1; D066298:In Vitro Techniques; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology
D007328:Insulin; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2