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1.
Cell Rep Med ; 4(3): 100959, 2023 03 21.
Article in English | MEDLINE | ID: mdl-36863336

ABSTRACT

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1 week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for ß cell replacement including the use of SC-islets or other types of novel cells in clinical settings.


Subject(s)
Islets of Langerhans Transplantation , Islets of Langerhans , Animals , Omentum/surgery , Islets of Langerhans/surgery , Islets of Langerhans/metabolism , Transplantation, Homologous , Islets of Langerhans Transplantation/adverse effects , Islets of Langerhans Transplantation/pathology , Primates , Allografts
2.
Sci Adv ; 8(19): eabm9881, 2022 05 13.
Article in English | MEDLINE | ID: mdl-35559682

ABSTRACT

Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3+ cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in ß cell replacement for treating type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1 , Islets of Langerhans Transplantation , Microgels , Allografts/metabolism , Animals , Diabetes Mellitus, Type 1/therapy , Islets of Langerhans Transplantation/methods , Primates , Sirolimus , Streptavidin
3.
Am J Transplant ; 22(3): 966-972, 2022 03.
Article in English | MEDLINE | ID: mdl-34704352

ABSTRACT

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1 , Hematopoietic Stem Cell Transplantation , Islets of Langerhans Transplantation , Islets of Langerhans , Animals , Diabetes Mellitus, Type 1/surgery , Glycemic Control , Graft Survival , Islets of Langerhans Transplantation/methods , Primates
4.
Curr Pharm Biotechnol ; 22(4): 501-507, 2021.
Article in English | MEDLINE | ID: mdl-32520685

ABSTRACT

OBJECTIVE: Lectin-like adhesins of enteric bacterial pathogens such as Escherichia coli are an attractive target for vaccine or drug development. Here, we have developed e-Membranome as a database of genome-wide putative adhesins in Escherichia coli (E. coli). METHODS: The outer membrane adhesins were predicted from the annotated genes of Escherichia coli strains using the PSORTb program. Further analysis was performed using Interproscan and the String database. The candidate proteins can be investigated for homology modeling of the Three-Dimensional (3D) structure (I-TASSER version 5.1), epitope region (ABCpred), and the glycan array. RESULTS: e-Membranome is implemented using the Django (version 2.2.5) framework. The Web Application Server Apache Tomcat 6.0 is integrated into the platform on Ubuntu Linux (version 16.04). MySQL database (version 5.7) is used as a database engine. The information on homology model of the 3D structure, epitope region, and affinity information from the glycan array will be stored in the e- Membranome database. As a case study, we performed a genome-wide screening of outer membraneembedded proteins from the annotated genes of E. coli using the e-Membranome pipeline. CONCLUSION: This platform is expected to be a valuable resource for advancing research of outer membrane proteins for the construction of lectin-glycan interaction network of E. coli. In addition, the e- Membranome pipeline can be extended to other similar biological systems that need to address hostpathogen interactions.


Subject(s)
Bacterial Outer Membrane Proteins/genetics , Escherichia coli/genetics , Genome-Wide Association Study , Adhesins, Bacterial/drug effects , Adhesins, Bacterial/genetics , Bacterial Outer Membrane Proteins/immunology , Computer Simulation , Databases, Factual , Enterohemorrhagic Escherichia coli/genetics , Epitopes , Escherichia coli/immunology , Escherichia coli Infections/genetics , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics , Escherichia coli Vaccines , Humans , Lectins , Polysaccharides/chemistry
5.
Cell Transplant ; 24(8): 1599-1614, 2015.
Article in English | MEDLINE | ID: mdl-24612609

ABSTRACT

The role of the novel costimulatory molecule TIM4 in anti-islet response is unknown. We explored TIM4 expression and targeting in Th1 (BALB/c islets into C57BL/6 mice) and Th2 (BALB/c islets into Tbet(-/-) C57BL/6 mice) models of anti-islet alloimmune response and in a model of anti-islet autoimmune response (diabetes onset in NOD mice). The targeting of TIM4, using the monoclonal antibody RMT4-53, promotes islet graft survival in a Th1 model, with 30% of the graft surviving in the long term; islet graft protection appears to be mediated by a Th1 to Th2 skewing of the immune response. Differently, in the Th2 model, TIM4 targeting precipitates graft rejection by further enhancing the Th2 response. The effect of anti-TIM4 treatment in preventing autoimmune diabetes was marginal with only minor Th1 to Th2 skewing. B-Cell depletion abolished the effect of TIM4 targeting. TIM4 is expressed on human B-cells and is upregulated in diabetic and islet-transplanted patients. Our data suggest a model in which TIM4 targeting promotes Th2 response over Th1 via B-cells. The targeting of TIM4 could become a component of an immunoregulatory protocol in clinical islet transplantation, aiming at redirecting the immune system toward a Th2 response.


Subject(s)
Autoimmunity , Islets of Langerhans Transplantation/immunology , Membrane Proteins/metabolism , Th2 Cells/immunology , Adult , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Differentiation , Cytokines/analysis , Cytokines/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/surgery , Diabetes Mellitus, Type 1/surgery , Female , Graft Survival/immunology , Humans , Islets of Langerhans/pathology , Male , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Middle Aged , Survival Rate , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/cytology , Th2 Cells/metabolism , Transcriptome , Transplantation, Homologous
6.
Physiol Plant ; 146(4): 439-47, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22540231

ABSTRACT

Relative changes in cell turgor of leaves of well-watered tomato plants were evaluated using the leaf patch clamp pressure probe (LPCP) under dynamic greenhouse climate conditions. LPCP changes, a measure for relative changes in cell turgor, were monitored at three different heights of transpiring and non-transpiring leaves of tomato plants on sunny and cloudy days simultaneously with whole plant water uptake. Clear diel patterns were observed for relative changes of cell turgor of both transpiring and non-transpiring leaves, which were stronger on sunny days than on cloudy days. A clear effect of canopy height was also observed. Non-transpiring leaves showed relative changes in cell turgor that closely followed plant water uptake throughout the day. However, in the afternoon the relative changes of cell turgor of the transpiring leaves displayed a delayed response in comparison to plant water uptake. Subsequent recovery of cell turgor loss of transpiring leaves during the following night appeared insufficient, as the pre-dawn turgescent state similar to the previous night was not attained.


Subject(s)
Patch-Clamp Techniques/methods , Plant Cells/physiology , Plant Leaves/physiology , Solanum lycopersicum/physiology , Biological Transport , Biomechanical Phenomena , Solanum lycopersicum/radiation effects , Patch-Clamp Techniques/instrumentation , Plant Leaves/radiation effects , Plant Transpiration , Pressure , Sunlight , Temperature , Water/physiology
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