OBJECTIVETo review the current status and progress on pig islet xenotransplantation.

DATA SOURCESData used in this review were mainly from English literature of Pubmed database. The search terms were "pig islet" and "xenotransplantation".

STUDY SELECTIONThe original articles and critical reviews selected were relevant to this review's theme.

RESULTSPigs are suggested to be an ideal candidate for obtaining available islet cells for transplantation. However, the potential clinical application of pig islet is still facing challenges including inadequate yield of high-quality functional islets and xenorejection of the transplants. The former can be overcome mainly by selection of a suitable pathogen-free source herd and the development of isolation and purification technology. While the feasibility of successful preclinical pig islet xenotranplantation provides insights in the possible mechanisms of xenogeneic immune recognition and rejection to overwhelm the latter. In addition, the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies is promising.

CONCLUSIONSPig islet xenotransplantation is one of the prospective treatments to bridge the gap between the needs of transplantation in patients with diabetes and available islet cells. Nonetheless, further studies and efforts are needed to translate obtained findings into tangible applications.

Animals ; Graft Rejection ; immunology ; prevention & control ; Islets of Langerhans Transplantation ; immunology ; methods ; Swine ; Transplantation, Heterologous ; methods

OBJECTIVETo obtain massive human pancreatic islets with modified techniques and evaluation of the islets for the clinical allo-transplantation to treat type I and II diabetes.

METHODS28 consecutive adult human pancreata were isolated with modified automated techniques. Islets were purified using continuous density gradient. The islet yield was counted with international standard known as islet equivalent (IEQ). The function of the isolated islets was evaluated by measuring DNA/insulin ratio, static glucose stimulating test in vitro and transplanting the islets into diabetic nude mice in vivo followed by abdominal glucose tolerance test and C peptide measurement.

RESULTSThe yield of 28 consecutive human pancreata isolations ranged from 5 000 to 1 030 000 IEQs/pancreas with the average of 291 635 IEQs/pancreas. The first 13 isolations yielded 49 123 IEQs/pancreas, 846 IEQs/g and, purity 87% in average. The remained 15 isolations after the modifications yielded 501 813 IEQs/pancreas, 7 003 IEQs/g and purity 89% in average. The results of in vitro SGS showed good response to the different glucose concentration. 34 diabetic nude mice were transplanted under the renal capsule with the freshly isolated islets. 29 out of 34 diabetic mice obtained normoglycemia within 12 hours and the glucose tolerance tests were near normal. Serum C peptide level of transplanted mice is close to that of the control group.

CONCLUSIONSMassive human islets can be isolated with the modified techniques. Quality assessment of these islets both in vitro and in vivo has indicated that these high quality human islets could be used for the clinical allogeneic islet transplantation.

Adult ; Animals ; Cell Separation ; methods ; Diabetes Mellitus, Experimental ; surgery ; Glucose ; Humans ; In Vitro Techniques ; Islets of Langerhans ; cytology ; drug effects ; physiology ; Islets of Langerhans Transplantation ; Mice ; Mice, Nude ; Transplantation, Heterologous

Up till 2000 when Edmonton group introduced islet transplant procedure in conjunction with a novel glucocorticoid-free immunosuppressive regimen rendering 100% (n=7) of patients with type 1 diabetes insulin-independent for at least 1 year, islet transplant was taken into the clinic. Although significant progress in clinical islet transplant has occurred during recent years, challenges remain, including shortage of available donor organs, technical aspects of islet preparation and transplantation, immunological rejection post-transplant, unclear long-term outcomes of islet transplantation. Special attention is given to current limitation in islet transplantation together with new possible strategies that raise expectations for the widespread use of islet transplantation in the future.
Diabetes Mellitus ; surgery ; Humans ; Immunosuppressive Agents ; therapeutic use ; Islets of Langerhans Transplantation ; immunology ; methods ; trends

BACKGROUNDGlobally, 180 million people suffer from diabetes mellitus. Islet transplantation is believed to be an almost ideal therapy for insulin-dependent patients. How to maintain the viability and the function of isolated human islets is a challenge in clinical practice. Sertoli cells are considered 'nurse cells' in the seminiferous tubules and have been used in cell graft protocols for neurodegenerative diseases and diabetes in many studies. Many researchers have used immature murine testes as the primarily source of Sertoli cells in islet transplantation because they are easily purified. Mature human Sertoli cells have been seldom investigated. In the present study, we developed a method for the isolation and culture of Sertoli cells derived from adult human testes, and investigated their effects on the function of allogeneic islets when they were cultured together in vitro.

METHODSAdult Sertoli cells were prepared successfully by two-step enzyme digestion with trypsin, collagenase and hyaluronidase. They were identified by morphological characteristics and their activity was determined by MTT colorimetry over a 28-day culture time in vitro. A glucose-stimulated insulin secretion test was performed to detect the effects of Sertoli cells on allogeneic islets' function when they were co-cultured for 21 days in vitro.

RESULTSIn cultured cells, mature human Sertoli cells accounted for more than 90% of total cells. The activity of Sertoli cells reached 95% and they remained highly cytoactive for a long time in vitro (P > 0.05). Compared with the islets cultured alone, the co-cultured islets with allogeneic Sertoli cells maintained higher sensitivity to glucose stimulation for the duration of the experiment (P < 0.01).

CONCLUSIONSA method of isolation and culture of Sertoli cells from adult testes has been established. Sertoli cells could enhance allogeneic islets' function when they were co-cultured in vitro. They could be a helper cell in islet transplantation.

Adult ; Cell Separation ; methods ; Cell Survival ; Cells, Cultured ; Coculture Techniques ; Humans ; Islets of Langerhans ; physiology ; Islets of Langerhans Transplantation ; Male ; Sertoli Cells ; cytology ; physiology

In the conventional treatments of type I diabetes, there are various problems. As a new adequate treatment of diabetes, cell replacement therapy of diabetes has been applied and given research priority. We have investigated the applications of cell transplantation in the treatment of diabetes and have retrieved the relevant articles on cells transplantation for the treatment of diabetes. In this paper, we review the history, development, merits and demerits of cell transplantation and the recent advances in pancreatic islet transplantation research. The latest progress in the induction of stem cell to differentiate into the insulin-producing cells was also introduced.
Animals ; Diabetes Mellitus, Type 1 ; surgery ; therapy ; Humans ; Insulin-Secreting Cells ; cytology ; Islets of Langerhans Transplantation ; methods ; Stem Cell Transplantation

This paper reviewed recent advances in pancreatic islet transplantation research, including islet isolation, purification, culture, cryopreservation and immunoisolation. Latest progresses in induction of pancreatic stem cell and embryonic stem cell to differentiate into insulin-producing islets were also introduced. On the basis of the present situation and future development of islet transplantation-based therapies for diabetes, the author thought that allogeous islet transplantation is a main choice for type I diabetes today and pancreatic stem cell transplantation for tomorrow.
Animals ; Cell Separation ; Cells, Cultured ; Diabetes Mellitus, Type 1 ; therapy ; Humans ; Islets of Langerhans Transplantation ; methods ; Stem Cell Transplantation

Microencapsulation of cells or tissue fragments represents a potentially effective method to prevent graft rejection in allotransplantation and xenotransplantation without the need of immunosuppression, but the functional survival of all trial grafts is still limited. Usually, graft failure is mainly interpreted as the consequence of the progressive fibrotic overgrowth of capsules, the insufficient supply of oxygen and nutrition to the encapsulated graft, and the dysfunction of the encapsulated graft induced by small proinflammatory factors. These detrimental factors are interrelatd with the microcapsules, the implanted graft, and the transplantation site. This article reviews and summarizes the advance and the limitation of microencapsulated grafts transplantation in the above-mentioned aspects.
Alginates ; chemistry ; Animals ; Biocompatible Materials ; chemistry ; Capsules ; Graft Survival ; immunology ; Humans ; Islets of Langerhans Transplantation ; immunology ; methods ; physiology ; Transplantation, Heterologous ; immunology

Pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus. Here, we describe the first reported case of successful allogeneic islet transplantation alone, using single-donor, marginal-dose islets in a Korean patient. A 59-yr-old patient with type 1 diabetes mellitus, who suffered from recurrent severe hypoglycemia, received 4,163 islet equivalents/kg from a single brain-death donor. Isolated islets were infused intraportally without any complications. The immunosuppressive regimen was based on the Edmonton protocol, but the maintenance dosage was reduced because of mucositis and leukopenia. Although insulin independence was not achieved, the patient showed stabilized blood glucose concentration, reduced insulin dosage and reversal of hypoglycemic unawareness, even with marginal dose of islets and reduced immunosuppressant. Islet transplantation may successfully improve endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus.
Blood Glucose/analysis ; Diabetes Mellitus, Type 1/*surgery ; Female ; Humans ; Hypoglycemia/*surgery ; Immunosuppression/methods ; Immunosuppressive Agents/therapeutic use ; Islets of Langerhans/physiology/*surgery ; Islets of Langerhans Transplantation/*methods ; Middle Aged ; Republic of Korea ; Tissue Donors

OBJECTIVE: To evaluate transplanted porcine pancreatic islets in the kidney capsules of diabetic mice using a clinically approved superparamagnetic iron oxide (SPIO) and a 1.5T MR scanner. MATERIALS AND METHODS: Various numbers of porcine pancreatic islets labeled with Resovist, a carboxydextran-coated SPIO, were transplanted into the kidney capsules of normal mice and imaged with a 3D FIESTA sequence using a 1.5T clinical MR scanner. Labeled (n = 3) and unlabeled (n = 2) islets were transplanted into the kidney capsules of streptozotocin-induced diabetic mice. Blood glucose levels and MR signal intensities were monitored for 30 days post-transplantation. RESULTS: There were no significant differences in viability or insulin secretion between labeled and unlabeled islets. A strong correlation (r2 > 0.94) was evident between the number of transplanted islets and T2 relaxation times quantified by MRI. Transplantation with labeled or unlabeled islets helped restore normal sustained glucose levels in diabetic mice, and nephrectomies induced the recurrence of diabetes. The MR signal intensity of labeled pancreatic islets decreased by 80% over 30 days. CONCLUSION: The transplantation of SPIO-labeled porcine islets into the kidney capsule of diabetic mice allows to restore normal glucose levels, and these islets can be visualized and quantified using a 1.5T clinical MR scanner.
Animals ; Contrast Media/pharmacology ; Dextrans/pharmacology ; Diabetes Mellitus, Experimental/*therapy ; Glucose Tolerance Test ; *Islets of Langerhans Transplantation ; Magnetic Resonance Imaging/*methods ; Magnetite Nanoparticles ; Mice ; Microscopy, Electron ; Statistics, Nonparametric ; Swine

BACKGROUNDCostimulatory signals play a vital role in T cell activation. Blockade of costimulatory pathway by CTLA4Ig or CD40LIg have enhanced graft survival in experimental transplantation models yet mechanisms remain undetermined. We investigated the effects of CTLA4Ig and CD40LIg gene transfer on islet xenografts rejection in rats.

METHODSHuman islets were infected with recombinant adenoviruses containing CTLA4Ig and CD40LIg genes and implanted beneath the kidney capsule of diabetic rats. Levels of blood sugar, morphological changes, and survival of grafts were recorded. Expressions of CTLA4Ig, CD40LIg and insulin were detected by immunohistochemical staining and cytokines levels were quantified by enzyme-linked immunosorbent assay (ELISA).

RESULTSBlood glucose levels in transplant rats decreased to normal level on the 2nd day post transplantation. The mean blood glucose in the control group, CTLA4Ig transfected group, CD40LIg transfected group and CTLA4Ig + CD40LIg cotransfected group increased on days 8, 24, 21, 68, post transplantation respectively. The grafts in control group, CTLA4Ig transfected group, CD40LIg transfected group and CTLA4Ig + CD40LIg cotransfected group survived for (8 ± 1), (29 ± 4), (27 ± 3), and (74 ± 10) days, respectively. Survival in CTLA4Ig + CD40LIg cotransfected group was significantly longer. Survivals of CTLA4Ig transfected group and CD40LIg transfected group were significantly longer than control group. In control animals, serum interleukin-2 and tumor necrosis factor α concentration significantly increased within seven days post transplantation. Haematoxylin eosin staining of grafts showed live islets in situ of transplant rats without inflammatory cell infiltration. Immunohistochemical staining confirmed the expression of insulin at islets in all experimental groups.

CONCLUSIONSTransfer of CTLA4Ig and CD40LIg genes, especially the cotransfer of both, inhibits rejection of murine islet xenografts. Downregulated expressions of Th1 cells related cytokines might be related to the beneficial effects.

Abatacept ; Animals ; Enzyme-Linked Immunosorbent Assay ; Graft Rejection ; therapy ; Graft Survival ; genetics ; physiology ; Humans ; Immunoconjugates ; genetics ; metabolism ; Immunohistochemistry ; Insulin ; metabolism ; Islets of Langerhans Transplantation ; immunology ; methods ; Rats ; Recombinant Fusion Proteins ; genetics ; metabolism ; Transplantation, Heterologous ; immunology ; methods