A whole-cell pertussis vaccine engineered to elicit reduced reactogenicity protects baboons against pertussis challenge.

Whole-cell pertussis (wP) vaccines introduced in the 1940s led to a dramatic reduction of pertussis incidence and are still widely used in low- and middle-income countries (LMICs) worldwide. The reactogenicity of wP vaccines resulted in reduced public acceptance, which drove the development and introduction of acellular pertussis (aP) vaccines in high-income countries in the 1990s. Increased incidence of pertussis disease has been observed in high-income countries following the introduction of aP vaccines despite near universal rates of pediatric vaccination.

Reversal of Experimental Autoimmune Diabetes With an sCD39/Anti-CD3 Treatment.

Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes. We then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies.

CCL21 Expression in β-Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice.

Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes.

Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice.

Unfortunately there is a mistake in the presentation of the affiliations in this paper.

In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice.

Aims/hypothesis: Autoimmune attack against the insulin-producing beta cells in the pancreatic islets results in type 1 diabetes. However, despite considerable research, details of the type 1 diabetes immunopathology in situ are not fully understood mainly because of difficult access to the pancreatic islets in vivo.

Methods: Here, we used direct non-invasive confocal imaging of islets transplanted in the anterior chamber of the eye (ACE) to investigate the anti-islet autoimmunity in NOD mice before, during and after diabetes onset.

Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point.

Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans.

The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model.

Unlabelled: Islet transplantation is a promising therapy for Type 1 diabetes mellitus; however, host inflammatory and immune responses lead to islet dysfunction and destruction, despite potent systemic immunosuppression. Grafting of poly(ethylene glycol) (PEG) to the periphery of cells or tissues can mitigate inflammation and immune recognition via generation of a steric barrier. Herein, we sought to evaluate the complementary impact of islet PEGylation with a short-course immunotherapy on the survival of fully-MHC mismatched islet allografts (DBA/2 islets into diabetic C57BL/6J recipients).

Effects of Composition of Alginate-Polyethylene Glycol Microcapsules and Transplant Site on Encapsulated Islet Graft Outcomes in Mice.

Background: Understanding the effects of capsule composition and transplantation site on graft outcomes of encapsulated islets will aid in the development of more effective strategies for islet transplantation without immunosuppression.

Methods: Here, we evaluated the effects of transplanting alginate (ALG)-based microcapsules (Micro) in the confined and well-vascularized epididymal fat pad (EFP) site, a model of the human omentum, as opposed to free-floating in the intraperitoneal cavity (IP) in mice. We also examined the effects of reinforcing ALG with polyethylene glycol (PEG).

Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold.

Transplantation of pancreatic islets is a therapeutic option to preserve or restore β-cell function. Our study was aimed at developing a clinically applicable protocol for extrahepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ-generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and nonhuman primate (NHP) models.

Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice.

With a view toward reduction of graft loss, we explored pancreatic islet transplantation within fibrin matrices rendered pro-angiogenic by incorporation of minimal doses of vascular endothelial growth factor-A165 and platelet-derived growth factor-BB presented complexed to a fibrin-bound integrin-binding fibronectin domain. Engineered matrices allowed for extended release of pro-angiogenic factors and for their synergistic signaling with extracellular matrix-binding domains in the post-transplant period. Aprotinin addition delayed matrix degradation and prolonged pro-angiogenic factor availability within the graft.

Device design and materials optimization of conformal coating for islets of Langerhans.

Encapsulation of islets of Langerhans may represent a way to transplant islets in the absence of immunosuppression. Traditional methods for encapsulation lead to diffusional limitations imposed by the size of the capsules (600-1,000 μm in diameter), which results in core hypoxia and delayed insulin secretion in response to glucose. Moreover, the large volume of encapsulated cells does not allow implantation in sites that might be more favorable to islet cell engraftment.

MicroRNAs in islet immunobiology and transplantation.

The ultimate goal of diabetes therapy is the restoration of physiologic metabolic control. For type 1 diabetes, research efforts are focused on the prevention or early intervention to halt the autoimmune process and preserve β cell function. Replacement of pancreatic β cells via islet transplantation reestablishes physiologic β cell function in patients with diabetes.

Transdisciplinary approach to restore pancreatic islet function.

The focus of our research is on islet immunobiology. We are exploring novel strategies that could be of assistance in the treatment and prevention of type 1 diabetes, as well as in the restoration of metabolic control via transplantation of insulin producing cells (i.e.

Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.

Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice.

Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7.

Background: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement.

Macroporous three-dimensional PDMS scaffolds for extrahepatic islet transplantation.

Clinical islet transplantation has demonstrated success in treating type 1 diabetes. A current limitation is the intrahepatic portal vein transplant site, which is prone to mechanical stress and inflammation. Transplantation of pancreatic islets into alternative sites is preferable, but challenging, as it may require a three-dimensional vehicle to confer mechanical protection and to confine islets to a well-defined, retrievable space where islet neovascularization can occur.

Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets.

Nonspecific inflammation in the transplant microenvironment results in β-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets.

Prevention of autoimmune diabetes and induction of β-cell proliferation in NOD mice by hyperbaric oxygen therapy.

We evaluated the effects of hyperbaric oxygen therapy (HOT) on autoimmune diabetes development in nonobese diabetic (NOD) mice. Animals received no treatment or daily 60-min HOT 100% oxygen (HOT-100%) at 2.0 atmospheres absolute and were monitored for diabetes onset, insulitis, infiltrating cells, immune cell function, and β-cell apoptosis and proliferation.

Beneficial effects of ischemic preconditioning on pancreas cold preservation.

Ischemic preconditioning (IPC) confers tissue resistance to subsequent ischemia in several organs. The protective effects are obtained by applying short periods of warm ischemia followed by reperfusion prior to extended ischemic insults to the organs. In the present study, we evaluated whether IPC can reduce pancreatic tissue injury following cold ischemic preservation.

Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells.

We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on stepwise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human C-peptide production in response to a glucose challenge.

Antisense miR-7 impairs insulin expression in developing pancreas and in cultured pancreatic buds.

MicroRNAs regulate gene expression by inhibiting translation or inducing target mRNA degradation. MicroRNAs regulate organ differentiation and embryonic development, including pancreatic specification and islet function. We showed previously that miR-7 is highly expressed in human pancreatic fetal and adult endocrine cells.

Donor islet endothelial cells in pancreatic islet revascularization.

Objective: Freshly isolated pancreatic islets contain, in contrast to cultured islets, intraislet endothelial cells (ECs), which can contribute to the formation of functional blood vessels after transplantation. We have characterized how donor islet endothelial cells (DIECs) may contribute to the revascularization rate, vascular density, and endocrine graft function after transplantation of freshly isolated and cultured islets.

Research Design And Methods: Freshly isolated and cultured islets were transplanted under the kidney capsule and into the anterior chamber of the eye.

Targeted deletion of one or two copies of the G protein β subunit Gβ5 gene has distinct effects on body weight and behavior in mice.

We investigated the physiological role of Gβ5, a unique G protein β subunit that dimerizes with regulators of G protein signaling (RGS) proteins of the R7 family instead of Gγ. Gβ5 is essential for stability of these complexes, so that its knockout (KO)causes degradation of the entire Gβ5-R7 family. We report that the Gβ5-KO mice remain leaner than the wild type (WT) throughout their lifetime and are resistant to a high-fat diet.

Prolactin supplementation to culture medium improves beta-cell survival.

Objectives: Recent studies demonstrated that prolactin (PRL) has beneficial effects on beta cells for islet transplantation. We examined the effect of human recombinant PRL (rhPRL) supplementation to the culture media to determine its potential use in the context of clinical islet transplantation.

Materials And Methods: Each human islet isolated from 14 deceased multiorgan donors was cultured in Miami modified media-1 supplemented with or without rhPRL (500 microg/L) for 48 hr.