Islet transplantation tolerance in animals with defined histocompatibility and diabetes

Advances in organ transplantation benefit from development of genetically inbred animal strains with defined histocompatibility and cell-specific markers to distinguish donor and host cell subsets. For studies of pancreatic islet transplantation tolerance in diabetes, an invariant method to ablate host β cells and induce diabetes would provide an immense additional advantage. Here we detail development and use of B6 RIP-DTR mice , an immunocompetent line permitting diabetes induction with 100% penetrance. This inbred line is homozygous for the C57BL/6J major histocompatibility complex (MHC) haplotype and expresses the mutant CD45.1 allele in the hematopoietic lineage. β cell-specific expression of a high-affinity receptor for diphtheria toxin (DT) permits experimental β cell ablation and diabetes induction after DT administration. Diabetes reversal for over one year was achieved after transplantation with congenic C57BL/6J islets, but not with MHC-mismatched BALB/c islets, which were rapidly rejected. In summary, the generation of a C57BL/6J congenic line harboring the CD45.1 allele and Ins2-HBEGF transgene should advance studies of islet transplantation tolerance and mechanisms to improve islet engraftment and function, thereby optimizing development of cell replacement strategies for diabetes mellitus.

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Role of Exosomes in Islet Transplantation

Frontiers in Endocrinology ◽

10.3389/fendo.2021.681600 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jordan Mattke ◽

Srividya Vasu ◽

Carly M. Darden ◽

Kenjiro Kumano ◽

Michael C. Lawrence ◽

...

Keyword(s):

Islet Transplantation ◽

Graft Function ◽

Pancreatic Islet Transplantation ◽

Complex Molecules ◽

Wide Range ◽

And Function ◽

Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

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Using β-Cell Growth Factors to Enhance Human Pancreatic Islet Transplantation*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.3.7315 ◽

2001 ◽

Vol 86 (3) ◽

pp. 984-988 ◽

Cited By ~ 4

Author(s):

Adolfo García-Ocaña ◽

Rupangi C. Vasavada ◽

Karen K. Takane ◽

Ana Cebrian ◽

Juan Carlos Lopez-Talavera ◽

...

Keyword(s):

Growth Factors ◽

Cell Growth ◽

Islet Transplantation ◽

Pancreatic Islet ◽

Pancreatic Islet Transplantation ◽

Β Cell ◽

Human Pancreatic Islet

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Hemoglobin A1C Percentage in Nonhuman Primates: A Useful Tool to Monitor Diabetes before and after Porcine Pancreatic Islet Xenotransplantation

Journal of Transplantation ◽

10.1155/2011/965605 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Marco Marigliano ◽

Anna Casu ◽

Suzanne Bertera ◽

Massimo Trucco ◽

Rita Bottino

Keyword(s):

Islet Transplantation ◽

Pancreatic Islet ◽

Hemoglobin A1c ◽

Diabetes Research ◽

Pancreatic Islet Transplantation ◽

Porcine Islet ◽

Islet Xenotransplantation ◽

Before And After ◽

Islet Transplants ◽

Diabetes Induction

Non-human primates (NHPs) are a very valuable experimental model for diabetes research studies including experimental pancreatic islet transplantation. In particular NHPs are the recipients of choice to validate pigs as possible source of pancreatic islets. The aim of this study was to quantify glycated hemoglobin percentage in NHPs and to assess whether changes in values reflect the metabolic trends after diabetes induction and islet transplantation. Sera from 15 NHPs were analyzed. 9 NHPs were rendered diabetic with streptozotocin (STZ), and 3 of them received porcine islet transplants. Hemoglobin A1c (HbA1c) percentage was measured with an assay based on a latex immunoagglutination inhibition methodology. Whereas diabetes and its duration were associated with increasing HbA1c levels, postislet transplantation blood glucose normalization was paralleled by a decrease in the HbA1c percentage. Our data provide evidence that HbA1c is a useful tool to monitor glucose metabolism in NHPs.

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Loss of end-differentiated β-cell phenotype following pancreatic islet transplantation

American Journal of Transplantation ◽

10.1111/ajt.14521 ◽

2017 ◽

Vol 18 (3) ◽

pp. 750-755 ◽

Cited By ~ 6

Author(s):

S. J. Anderson ◽

M. G. White ◽

S. L. Armour ◽

R. Maheshwari ◽

D. Tiniakos ◽

...

Keyword(s):

Islet Transplantation ◽

Pancreatic Islet ◽

Cell Phenotype ◽

Pancreatic Islet Transplantation ◽

Β Cell

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Microfluidics for Live-Cell Imaging Pancreatic Islets of Langerhans for Human Transplant

Volume 1A, Symposia: Advances in Fluids Engineering Education; Turbomachinery Flow Predictions and Optimization; Applications in CFD; Bio-Inspired Fluid Mechanics; Droplet-Surface Interactions; CFD Verification and Validation; Development and Applications of Immersed Boundary Methods; DNS, LES, and Hybrid RANS/LES Methods ◽

10.1115/fedsm2014-21159 ◽

2014 ◽

Author(s):

Joshua E. Mendoza-Elias ◽

José Oberholzer ◽

Yong Wang

Keyword(s):

Islet Transplantation ◽

Pancreatic Islet ◽

Live Cell Imaging ◽

Cell Imaging ◽

Islet Cells ◽

Live Cell ◽

Cell Physiology ◽

Type I ◽

Pancreatic Islet Transplantation ◽

Β Cell

Since the introduction of the Edmonton Protocol in 2000, islet transplantation has been emerging as promising therapy for Type I diabetes mellitus (T1DM) and currently is the only therapy that can achieve glycemic control without the need for exogenous insulin. Transplanting islet cells has several advantages over transplanting a whole pancreas in that it involves only a minor surgical procedure with low morbidity and mortality, and at a significantly lower cost. However, an obstacle to realizing this goal is a lack of an islet potency index as required by the U.S. Food and Drug Administration (FDA) biologics licensing, as well as a more complete understanding of the physiological mechanisms governing islet and β-cell physiology. Recently, the University of Illinois at Chicago (UIC) has developed a microfluidic platform that can mimic in vivo islet microenvironments through precise and dynamic control of perifusing culture media and oxygen culture levels; all while measuring functionally relevant factors including intracellular calcium levels, mitochondrial potentials, and insulin secretion. By developing an understanding of the physiology and pathophysiology of islets we can more effectively develop strategies that reduce metabolic stress and promote optimization in order to achieve improved success of islet transplantation and open new clinical avenues. The presentation begins by introducing key issues in the field of pancreatic islet transplantation as a clinical therapy for T1DM. This is followed by brief review various technologies that have been developed to study islet cells. The presentation then describes the design, application, and evolution of UIC’s microfluidic-based multimodal islet perifusion and live-cell imaging system for the study of pancreatic islet and β-cell physiology. The article then concludes presenting initial findings from studies seeking to develop an islet potency test.

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Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation

Thrombosis and Haemostasis ◽

10.1160/th15-05-0429 ◽

2016 ◽

Vol 115 (04) ◽

pp. 781-788 ◽

Cited By ~ 25

Author(s):

Jong-Hyung Lim ◽

Ioannis Mitroulis ◽

Anaisa Ferreira ◽

Lan-Sun Chen ◽

Bettina Gercken ◽

...

Keyword(s):

Endothelial Cell ◽

Islet Transplantation ◽

Inflammatory Reaction ◽

Aggregate Formation ◽

Pancreatic Islet Transplantation ◽

Inflammatory Injury ◽

Novel Approach ◽

Peptide Release ◽

Pre Treatment ◽

And Function

SummaryPlatelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood–islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.Supplementary Material to this article is available online at www.thrombosis-online.com.

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In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00073.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. E650-E661 ◽

Cited By ~ 7

Author(s):

Clarissa Hernandez Stephens ◽

Kara S. Orr ◽

Anthony J. Acton ◽

Sarah A. Tersey ◽

Raghavendra G. Mirmira ◽

...

Keyword(s):

Islet Transplantation ◽

Cellular Therapy ◽

Foreign Body Response ◽

Type I ◽

Pancreatic Islet Transplantation ◽

And Function

Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 –3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.

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