Recombinant Lactococcus lactis Carrying IL-4 and IL-10 Coding Vectors Protects against Type 1 Diabetes in NOD Mice and Attenuates Insulitis in the STZ-Induced Model

Type 1 diabetes (T1D) is an autoimmune disease that culminates in beta cell destruction in the pancreas and, subsequently, deficiency in insulin production. Cytokines play a crucial role in the development of diabetes, orchestrating the recruitment and action of immune cells, to not only destroy insulin-producing cells but also preserve them. Therefore, the aim of this study was to investigate the effect of orally administered Lactococcus lactis MG1363 FnBPA+ strains carrying plasmids encoding IL-4 and IL-10 in the streptozotocin- (STZ-) induced diabetes model and in nonobese diabetic (NOD) mice. The STZ-induced mice that were treated with combined bacterial strains carrying plasmids encoding IL-4 and IL-10 showed lower incidence of diabetes and more preserved pancreatic islets than the mice that received the individual bacterial strains. Combined administration of L. lactis MG1363 FnBPA+ (pValac::dts::IL-4) and L. lactis MG1363 FnBPA+ (pValac::IL-10) resulted in protection against diabetes in NOD mice. It was shown that the combined treatment with recombinant bacterial by oral route prevented hyperglycemia and reduced the pancreatic islets-destruction in NOD mice. In addition, increased levels of IL-4 and IL-10 in serum and pancreatic tissue revealed a systemic effect of the treatment and also favored an anti-inflammatory microenvironment. Reduced concentrations of IL-12 in pancreas were essential to the regulation of inflammation, resulting in no incidence of diabetes in treated NOD mice. Normal levels of intestinal sIgA after long-term treatment with the L. lactis strains carrying plasmids encoding IL-4 and IL-10 indicate the development of oral tolerance and corroborate the use of this potent tool of mucosal delivery. For the first time, L. lactis MG1363 FnBPA+ strains carrying eukaryotic expression vectors encoding IL-4 and IL-10 are tested in STZ-induced and NOD mouse models. Therefore, our study demonstrates this innovative strategy provides immunomodulatory potential for further investigations in T1D and other autoimmune diseases.

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Development of a Bioartificial Vascular Pancreas

Journal of Tissue Engineering ◽

10.1177/20417314211027714 ◽

2021 ◽

Vol 12 ◽

pp. 204173142110277

Author(s):

Edward X Han ◽

Juan Wang ◽

Mehmet Kural ◽

Bo Jiang ◽

Katherine L Leiby ◽

...

Keyword(s):

Type 1 Diabetes ◽

Pancreatic Islets ◽

Vascular Graft ◽

Term Treatment ◽

Diffusion Limitations ◽

Human Scale ◽

Arterial Blood ◽

Long Term Treatment

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

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Natural Protection From Type 1 Diabetes in Non Obese Diabetic (Nod) Mice is Characterized by a Unique Pancreatic Islet Phenotype

10.2337/figshare.13643393 ◽

2021 ◽

Author(s):

Joanne Boldison ◽

Terri C. Thayer ◽

Joanne Davies ◽

F. Susan Wong

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Pancreatic Islets ◽

Pancreatic Islet ◽

Nod Mice ◽

Significant Shift ◽

Immune Infiltrate ◽

Cell Compartments ◽

Natural Protection

The non-obese diabetic (NOD) mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally-protected from developing diabetes, and currently studies characterising this cohort are very limited. Here, using both immunofluorescence and multi-parameter flow cytometry we focus on the pancreatic islet morphology and immune infiltrate observed in naturally-protected NOD mice. We show that naturally-protected NOD mice are characterised by an increased frequency of insulin-containing, smaller sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed towards a regulatory phenotype in both T and B-cell compartments. Pancreatic islets have an increased frequency of IL-10 producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift towards reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally-protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.

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Oral delivery of staphylococcal nuclease by Lactococcus lactis prevents type 1 diabetes mellitus in NOD mice

Applied Microbiology and Biotechnology ◽

10.1007/s00253-017-8480-5 ◽

2017 ◽

Vol 101 (20) ◽

pp. 7653-7662 ◽

Cited By ~ 9

Author(s):

Junchao Lang ◽

Xiaoke Wang ◽

Kunfeng Liu ◽

Dongmei He ◽

Pancong Niu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Lactococcus Lactis ◽

Oral Delivery ◽

Nod Mice ◽

Staphylococcal Nuclease

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Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection

Virology ◽

10.1016/j.virol.2004.06.049 ◽

2004 ◽

Vol 329 (2) ◽

pp. 381-394 ◽

Cited By ~ 85

Author(s):

Kristen M. Drescher ◽

Ken Kono ◽

Shubhada Bopegamage ◽

Steven D. Carson ◽

Steven Tracy

Keyword(s):

Type 1 Diabetes ◽

Virus Infection ◽

Pancreatic Islets ◽

Nod Mice ◽

Coxsackievirus B3 ◽

Diabetes Development

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11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

Hormone and Metabolic Research ◽

10.1055/s-0043-112761 ◽

2017 ◽

Vol 49 (09) ◽

pp. 693-700 ◽

Cited By ~ 4

Author(s):

Ahmed Shehata ◽

Leticia Quintanilla-Fend ◽

Sabrina Bettio ◽

Zahra Kamyabi-Moghaddam ◽

Ursula Kohlhofer ◽

...

Keyword(s):

Animal Model ◽

Type 1 Diabetes ◽

Body Weight ◽

Pancreatic Islets ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Apoptotic Cells ◽

Boswellic Acid ◽

Human Type 1 Diabetes

Abstract11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.

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Natural Protection From Type 1 Diabetes in Non Obese Diabetic (Nod) Mice is Characterized by a Unique Pancreatic Islet Phenotype

10.2337/figshare.13643393.v1 ◽

2021 ◽

Author(s):

Joanne Boldison ◽

Terri C. Thayer ◽

Joanne Davies ◽

F. Susan Wong

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Pancreatic Islets ◽

Pancreatic Islet ◽

Nod Mice ◽

Significant Shift ◽

Immune Infiltrate ◽

Cell Compartments ◽

Natural Protection

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Deficiency in Type I Interferon Signaling Prevents the Early Interferon-Induced Gene Signature in Pancreatic Islets but Not Type 1 Diabetes in NOD Mice

Diabetes ◽

10.2337/db13-1210 ◽

2013 ◽

Vol 63 (3) ◽

pp. 1032-1040 ◽

Cited By ~ 24

Author(s):

H. S. Quah ◽

S. Miranda-Hernandez ◽

A. Khoo ◽

A. Harding ◽

S. Fynch ◽

...

Keyword(s):

Type 1 Diabetes ◽

Pancreatic Islets ◽

Type I Interferon ◽

Nod Mice ◽

Gene Signature ◽

Type I ◽

Interferon Signaling

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Oral administration of Lactococcus lactis-expressing heat shock protein 65 and tandemly repeated IA2P2 prevents type 1 diabetes in NOD mice

Immunology Letters ◽

10.1016/j.imlet.2016.04.008 ◽

2016 ◽

Vol 174 ◽

pp. 28-36 ◽

Cited By ~ 15

Author(s):

Kun-Feng Liu ◽

Xiao-Rui Liu ◽

Guo-Liang Li ◽

Shi-Ping Lu ◽

Liang Jin ◽

...

Keyword(s):

Type 1 Diabetes ◽

Heat Shock ◽

Heat Shock Protein ◽

Oral Administration ◽

Lactococcus Lactis ◽

Nod Mice ◽

Heat Shock Protein 65

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GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Biomedicines ◽

10.3390/biomedicines9010043 ◽

2021 ◽

Vol 9 (1) ◽

pp. 43

Author(s):

Jide Tian ◽

Blake Middleton ◽

Victoria Seunghee Lee ◽

Hye Won Park ◽

Zhixuan Zhang ◽

...

Keyword(s):

Type 1 Diabetes ◽

Gabab Receptor ◽

Combined Treatment ◽

Nod Mice ◽

Rna Seq ◽

Gaba Production ◽

Insulin Cells ◽

Suboptimal Dose ◽

Clinical Potential

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.

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