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Article ; Online: Towards antigen-specific Tregs for type 1 diabetes: Construction and functional assessment of pancreatic endocrine marker, HPi2-based chimeric antigen receptor.

Radichev, Ilian A / Yoon, Jeongheon / Scott, David W / Griffin, Kurt / Savinov, Alexei Y

2020 Volume 358, Page(s) 104224

Abstract: Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors. Recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease has ... ...

Abstract	Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors. Recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease has prompted us to design a novel Tregs-based antigen-specific T1D immunotherapy. We engineered a Chimeric Antigen Receptor (CAR) expressing a single-chain Fv recognizing the human pancreatic endocrine marker, HPi2. Human T cells, transduced with the resultant HPi2-CAR, proliferated and amplified Granzyme B accumulation when co-cultured with human, but not mouse β cells. Furthermore, following exposure of HPi2-CAR transduced cells to islets, CD8
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; Cell Line ; Diabetes Mellitus, Type 1/immunology ; Humans ; Immune Tolerance/immunology ; Immunotherapy, Adoptive/methods ; Islets of Langerhans ; Pancreas/cytology ; Pancreas/metabolism ; Protamines/immunology ; Protamines/metabolism ; Protein Engineering/methods ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; Single-Chain Antibodies/immunology ; Single-Chain Antibodies/metabolism ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Protamines ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Single-Chain Antibodies ; protamine 2
Language	English
Publishing date	2020-09-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2020.104224
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Article: Targeting the T-cell membrane type-1 matrix metalloproteinase-CD44 axis in a transferred type 1 diabetes model in NOD mice.

Savinov, Alexei Y / Strongin, Alex Y

Experimental and therapeutic medicine

2012 Volume 5, Issue 2, Page(s) 438–442

Abstract: This study tested the hypothesis that membrane-tethered type-1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific ... ...

Abstract	This study tested the hypothesis that membrane-tethered type-1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific and K(d)-restricted IS-CD8(+) cells. To confirm the importance of MT1-MMP proteolysis of CD44 in type 1 diabetes (T1D), the anti-diabetic effects of three MMP inhibitors (3(S)-2,2-dimethyl-4[4-pyridin-4-yloxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamate [AG3340], 2-(4-phenoxyphenylsulfonylmethyl) thiirane [SB-3CT] and epigallocatechin-3-gallate [EGCG]) were compared using an adoptive diabetes transfer model in non-obese diabetic (NOD) mice. Only AG3340 was capable of inhibiting both the activity of MT1-MMP and the shedding of CD44 in T cells; and the transendothelial migration and homing of IS-CD8(+) T cells into the pancreatic islets. SB-3CT and EGCG were incapable of inhibiting T cell MT1-MMP efficiently. As a result, AG3340 alone, but not SB-3CT or EGCG, delayed the onset of transferred diabetes in NOD mice. In summary, the results of the present study emphasize that the MT1-MMP-CD44 axis has a unique involvement in T1D development. Accordingly, we suggest that a potent small-molecule MT1-MMP antagonist is required for the design of novel therapies for T1D.
Language	English
Publishing date	2012-11-20
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2683844-8
ISSN	1792-1015 ; 1792-0981
ISSN (online)	1792-1015
ISSN	1792-0981
DOI	10.3892/etm.2012.821
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Article ; Online: Interference with islet-specific homing of autoreactive T cells: an emerging therapeutic strategy for type 1 diabetes.

Savinov, Alexei Y / Burn, Paul

Drug discovery today

2010 Volume 15, Issue 13-14, Page(s) 531–539

Abstract: Pathogenesis of type 1 diabetes involves the activation of autoimmune T cells, consequent homing of activated lymphocytes to the pancreatic islets and ensuing destruction of insulin-producing b cells. Interaction between activated lymphocytes and ... ...

Abstract	Pathogenesis of type 1 diabetes involves the activation of autoimmune T cells, consequent homing of activated lymphocytes to the pancreatic islets and ensuing destruction of insulin-producing b cells. Interaction between activated lymphocytes and endothelial cells in the islets is the hallmark of the homing process. Initial adhesion, firm adhesion and diapedesis of lymphocytes are the three crucial steps involved in the homing process. Cell-surface receptors including integrins, selectins and hyaluronate receptor CD44 mediate the initial steps of homing. Diapedesis relies on a series of proteolytic events mediated by matrix metalloproteinases. Here, molecular mechanisms governing transendothelial migration of the diabetogenic effector cells are discussed and resulting pharmacological strategies are considered.
MeSH term(s)	Animals ; Autoimmunity/drug effects ; Cell Movement/drug effects ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/etiology ; Diabetes Mellitus, Type 1/physiopathology ; Diabetes Mellitus, Type 1/prevention & control ; Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Islets of Langerhans/physiopathology ; T-Lymphocytes, Cytotoxic/drug effects
Chemical Substances	Hypoglycemic Agents
Language	English
Publishing date	2010-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2010.05.013
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Zs.A 4725: Show issues

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Article ; Online: Self-Transducible Bimodal PDX1-FOXP3 Protein Lifts Insulin Secretion and Curbs Autoimmunity, Boosting Tregs in Type 1 Diabetic Mice.

Amatya, Christina / Radichev, Ilian A / Ellefson, Jacob / Williams, Mark / Savinov, Alexei Y

Molecular therapy : the journal of the American Society of Gene Therapy

2017 Volume 26, Issue 1, Page(s) 184–198

Abstract: Type 1 diabetes (T1D) is characterized by massive destruction of insulin-producing β cells by autoreactive T lymphocytes, arising via defective immune tolerance. Therefore, effective anti-T1D therapeutics should combine autoimmunity-preventing and ... ...

Abstract	Type 1 diabetes (T1D) is characterized by massive destruction of insulin-producing β cells by autoreactive T lymphocytes, arising via defective immune tolerance. Therefore, effective anti-T1D therapeutics should combine autoimmunity-preventing and insulin production-restoring properties. We constructed a cell-permeable PDX1-FOXP3-TAT fusion protein (FP) composed of two transcription factors: forkhead box P3 (FOXP3), the master regulator of differentiation and functioning of self-tolerance-promoting Tregs, and pancreatic duodenal homeobox-1 (PDX1), the crucial factor supporting β cell development and maintenance. The FP was tested in vitro and in a non-obese diabetic mouse T1D model. In vitro, FP converted naive CD4
MeSH term(s)	Animals ; Autoimmunity ; Cellular Microenvironment/immunology ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/metabolism ; Disease Models, Animal ; Female ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Hepatocytes/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/immunology ; Insulin-Secreting Cells/metabolism ; Mice ; Mice, Inbred NOD ; Mice, Transgenic ; Phenotype ; Protein Binding ; Recombinant Fusion Proteins ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Trans-Activators/genetics ; Trans-Activators/metabolism
Chemical Substances	Forkhead Transcription Factors ; Foxp3 protein, mouse ; Homeodomain Proteins ; Recombinant Fusion Proteins ; Trans-Activators ; pancreatic and duodenal homeobox 1 protein
Language	English
Publishing date	2017-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2017.08.014
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Zs.A 5640: Show issues

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Article: Matrix metalloproteinases, T cell homing and beta-cell mass in type 1 diabetes.

Savinov, Alexei Y / Strongin, Alex Y

Vitamins and hormones

2008 Volume 80, Page(s) 541–562

Abstract: The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta ... ...

Abstract	The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.
MeSH term(s)	Animals ; Chemotaxis, Leukocyte/physiology ; Diabetes Mellitus, Type 1/metabolism ; Humans ; Insulin-Secreting Cells/physiology ; Matrix Metalloproteinases/metabolism ; Mice ; Rats ; T-Lymphocytes/physiology
Chemical Substances	Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2008-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/S0083-6729(08)00618-3
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Article: Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes.

Savinov, Alexei Y / Strongin, Alex Y

IUBMB life

2007 Volume 59, Issue 1, Page(s) 6–13

Abstract: Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally ... ...

Abstract	Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, beta-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes.
MeSH term(s)	Diabetes Mellitus, Type 1/enzymology ; Humans ; Hyaluronan Receptors/physiology ; Membrane Proteins/physiology ; Peptide Hydrolases/physiology ; T-Lymphocytes/enzymology
Chemical Substances	Hyaluronan Receptors ; Membrane Proteins ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2007-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1492141-8
ISSN	1521-6551 ; 1521-6543
ISSN (online)	1521-6551
ISSN	1521-6543
DOI	10.1080/15216540601187795
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Zs.A 1611: Show issues

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Article ; Online: Transgenic Overexpression of Tissue-Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification.

Savinov, Alexei Y / Salehi, Maryam / Yadav, Manisha C / Radichev, Ilian / Millán, José Luis / Savinova, Olga V

Journal of the American Heart Association

2015 Volume 4, Issue 12

Abstract: Background: Ectopic vascular calcification is a common condition associated with aging, atherosclerosis, diabetes, and/or chronic kidney disease. Smooth muscle cells are the best characterized source of osteogenic progenitors in the vasculature; however, ...

Abstract	Background: Ectopic vascular calcification is a common condition associated with aging, atherosclerosis, diabetes, and/or chronic kidney disease. Smooth muscle cells are the best characterized source of osteogenic progenitors in the vasculature; however, recent studies suggest that cells of endothelial origin can also promote calcification. To test this, we sought to increase the osteogenic potential of endothelial cells by overexpressing tissue-nonspecific alkaline phosphatase (TNAP), a key enzyme that regulates biomineralization, and to determine the pathophysiological effect of endothelial TNAP on vascular calcification and cardiovascular function. Methods and results: We demonstrated previously that mice transgenic for ALPL (gene encoding human TNAP) develop severe arterial medial calcification and reduced viability when TNAP is overexpressed in smooth muscle cells. In this study, we expressed the ALPL transgene in endothelial cells following endothelial-specific Tie2-Cre recombination. Mice with endothelial TNAP overexpression survived well into adulthood and displayed generalized arterial calcification. Genes associated with osteochondrogenesis (Runx2, Bglap, Spp1, Opg, and Col2a1) were upregulated in the aortas of endothelial TNAP animals compared with controls. Lesions in coronary arteries of endothelial TNAP mice showed immunoreactivity to Runx2, osteocalcin, osteopontin, and collagen II as well as increased deposition of sialoproteins revealed by lectin staining. By 23 weeks of age, endothelial TNAP mice developed elevated blood pressure and compensatory left ventricular hypertrophy with preserved ejection fraction. Conclusions: This study presented a novel genetic model demonstrating the osteogenic potential of TNAP-positive endothelial cells in promoting pathophysiological vascular calcification.
MeSH term(s)	Alkaline Phosphatase/metabolism ; Animals ; Calcinosis/etiology ; Calcinosis/metabolism ; Calcinosis/pathology ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Endothelium, Vascular/physiopathology ; Female ; Gene Expression ; Male ; Mice ; Mice, Transgenic ; Peripheral Arterial Disease/etiology ; Peripheral Arterial Disease/metabolism ; Peripheral Arterial Disease/pathology ; Real-Time Polymerase Chain Reaction
Chemical Substances	ALPL protein, mouse (EC 3.1.3.1) ; Alkaline Phosphatase (EC 3.1.3.1)
Language	English
Publishing date	2015-12-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.115.002499
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Article ; Online: Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes.

Radichev, Ilian A / Maneva-Radicheva, Lilia V / Amatya, Christina / Salehi, Maryam / Parker, Camille / Ellefson, Jacob / Burn, Paul / Savinov, Alexei Y

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 196, Issue 4, Page(s) 1495–1506

Abstract: Ag-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the costimulation step, have been associated with many autoimmune conditions, including type 1 diabetes ( ... ...

Abstract	Ag-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the costimulation step, have been associated with many autoimmune conditions, including type 1 diabetes (T1D). Recently, we demonstrated that the phenotype of impaired negative costimulation, due to reduced levels of V-set domain-containing T cell activation inhibitor 1 (VTCN1) protein on APCs, is shared between diabetes-susceptible NOD mice and human T1D patients. In this study, we show that a similar process takes place in the target organ, as both α and β cells within pancreatic islets gradually lose their VTCN1 protein during autoimmune diabetes development despite upregulation of the VTCN1 gene. Diminishment of functional islet cells' VTCN1 is caused by the active proteolysis by metalloproteinase N-arginine dibasic convertase 1 (NRD1) and leads to the significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, alternatively, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 negative costimulation, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti-islet T cell responses. This mechanism is tied to upregulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D.
MeSH term(s)	Animals ; Antigen Presentation ; Cytokines/biosynthesis ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/physiopathology ; Glucagon-Secreting Cells/immunology ; Humans ; Insulin-Secreting Cells/immunology ; Islets of Langerhans/immunology ; Islets of Langerhans/metabolism ; Lymphocyte Activation ; Metalloendopeptidases/antagonists & inhibitors ; Metalloendopeptidases/genetics ; Metalloendopeptidases/metabolism ; Mice, Inbred NOD ; Proteolysis ; T-Lymphocytes/immunology ; V-Set Domain-Containing T-Cell Activation Inhibitor 1/immunology ; V-Set Domain-Containing T-Cell Activation Inhibitor 1/metabolism
Chemical Substances	Cytokines ; V-Set Domain-Containing T-Cell Activation Inhibitor 1 ; VTCN1 protein, human ; Vtcn1 protein, mouse ; Metalloendopeptidases (EC 3.4.24.-) ; nardilysin (EC 3.4.24.61)
Language	English
Publishing date	2016-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1403251
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Article: Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes.

Frontiers in endocrinology

2021 Volume 12, Page(s) 737276

Abstract: Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial ...

Abstract	Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8
MeSH term(s)	CD8-Positive T-Lymphocytes/pathology ; Cell Differentiation/physiology ; Diabetes Mellitus, Type 1/pathology ; Humans ; Induced Pluripotent Stem Cells/pathology ; Insulin-Secreting Cells/pathology ; Islets of Langerhans/pathology
Language	English
Publishing date	2021-11-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2021.737276
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Article: Specific inhibition of autoimmune T cell transmigration contributes to beta cell functionality and insulin synthesis in non-obese diabetic (NOD) mice.

Savinov, Alexei Y / Rozanov, Dmitri V / Strongin, Alex Y

The Journal of biological chemistry

2007 Volume 282, Issue 44, Page(s) 32106–32111

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; C-Peptide/blood ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/immunology ; Glucose/metabolism ; Immunosuppressive Agents/therapeutic use ; Insulin/genetics ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Matrix Metalloproteinase 14 ; Matrix Metalloproteinase Inhibitors ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Organic Chemicals/therapeutic use ; RNA, Messenger/metabolism ; T-Lymphocytes/metabolism
Chemical Substances	C-Peptide ; Immunosuppressive Agents ; Insulin ; Matrix Metalloproteinase Inhibitors ; Mmp14 protein, mouse ; Organic Chemicals ; RNA, Messenger ; prinomastat (10T6626FRK) ; Matrix Metalloproteinase 14 (EC 3.4.24.80) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2007-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M705348200
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