Specific inhibition of autoimmune T cell transmigration contributes to beta cell functionality and insulin synthesis in non-obese diabetic (NOD) mice.
Human diabetes mellitus (IDDM; type I diabetes) is a T cell-mediated disease that is closely modeled in non-obese diabetic (NOD) mice. The pathogenesis of IDDM involves the transmigration of autoimmune T cells into the pancreatic islets and the subsequent destruction of insulin-producing beta cells. Therapeutic interventions leading to beta cell regeneration and the reversal of established IDDM are exceedingly limited. We report here that specific inhibition of T cell intra-islet transmigration by using a small molecule proteinase inhibitor restores beta cell functionality, increases insulin-producing beta cell mass, and alleviates the severity of IDDM in acutely diabetic NOD mice. As a result, acutely diabetic NOD mice do not require insulin injections for survival for a significant time period, thus providing a promising clue to effect IDDM reversal in humans. The extensive morphometric analyses and the measurements of both the C-peptide blood levels and the proinsulin mRNA levels in the islets support our conclusions. Diabetes transfer experiments suggest that the inhibitor specifically represses the T cell transmigration and homing processes as opposed to causing immunosuppression. Overall, our data provide a rationale for the pharmacological control of the T cell transmigration step in human IDDM.
Savinov
Alexei Y
AY
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Rozanov
Dmitri V
DV
Strongin
Alex Y
AY
D000818:Animals; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005947:Glucose / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009930:Organic Chemicals / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D002096:C-Peptide; D007166:Immunosuppressive Agents; D007328:Insulin; D061965:Matrix Metalloproteinase Inhibitors; C507096:Mmp14 protein, mouse; D009930:Organic Chemicals; D012333:RNA, Messenger; C113282:prinomastat; D053511:Matrix Metalloproteinase 14; D005947:Glucose