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- Jia, Xiaohui, et al.
(författare)
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Exendin-4 Increases the Expression of Hypoxia-InducibleFactor-1 in Rat Islets and Preserves the Endocrine CellVolume of Both Free and Macroencapsulated Islet Grafts
- 2012
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Ingår i: Cell Transplantation. - 0963-6897. ; 21:6, s. 1269-1283
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model.We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating thebeneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidneycapsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0–7). The mice were followed for 4 weeks andthe graft function andβ-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNAand protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined.Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graftfunction vs. 26% in controls,p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p =0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume,less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4, HIF-1αmRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treatedINS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginalislet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume.Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing theexpression of HIF-1
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| 2. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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A new oxygen carrier for improved long-term storage of human pancreata before islet isolation
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 89:2, s. 155-60
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.
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| 3. |
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| 4. |
- Caballero-Corbalán, José, et al.
(författare)
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Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation
- 2012
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 175:1, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Background. Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. Materials and Methods. Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. Results. Donor-and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% +/- 3.5% versus 24.8% +/- 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 +/- 5.0 versus 17.2 +/- 8.1 mu L/g, P = 0.004) and islet yield (1910 +/- 980 versus 3150 +/- 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. Conclusions. Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage. (C) 2012 Elsevier Inc. All rights reserved.
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| 5. |
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| 6. |
- Diab, Randa A H, et al.
(författare)
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Rat islets are not rejected by anti-islet antibodies in mice treated with costimulation blockade.
- 2014
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Ingår i: Xenotransplantation. - : Wiley. - 1399-3089 .- 0908-665X. ; 21:4, s. 353-66
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Tidskriftsartikel (refereegranskat)abstract
- Costimulation blockade can prevent rejection of islet xenografts in naïve but not sensitized recipients. Donor-specific antibodies (DSA) may partly explain this observation. The effect of DSA on rat islet xenograft survival in mice receiving costimulation blockade was investigated.
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| 7. |
- Friberg, Andrew S., et al.
(författare)
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Transplanted functional islet mass : donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:6, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Background.The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.Methods. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).Results.Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.Conclusion.The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.
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| 8. |
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| 9. |
- Sanner, Margareta, et al.
(författare)
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The kidney recipients' path to transplantation : A comparison between living and deceased kidney donor recipients in Stockholm, Sweden
- 2011
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 26:3, s. 1053-1057
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Much remains to be done to facilitate the transplantation process for patients with end-stage renal disease. The aim here was to explore these patients' experiences of the donation process and factors related to whether the actual donors of the recipients were living or deceased and describe which issues needed attention in a quality development project. Method. A specially constructed questionnaire was sent to 246 recipients of living and deceased kidney transplants who had been transplanted at the Karolinska University Hospital in Stockholm, Sweden. The response rate was 87%. RESULTS: Six conditions were identified as problematic:- Most living-donor kidney recipients perceived the evaluation period for the donors as too long. - Although a living donor was available, most living-donor kidney recipients had to undergo dialysis for a relatively long period. - A majority of the patients perceived it difficult to ask for a donation. Deceased-donor kidney recipients were least satisfied with the offered support in finding a living donor. - Patients perceived fear as the main reason for potential living donors to refuse donation. - About one-fourth of living-donor kidney recipients thought that the donors were abandoned by healthcare after nephrectomy. - Older patients and singles were least likely to receive a living-donor kidney. CONCLUSIONS: The problem issues outlined above should be scrutinized and improved. Checking these issues can be used in quality control when analysing living kidney donation at local and national levels.
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| 10. |
- Takahashi, Tohru, et al.
(författare)
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Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of foxp3+ regulatory T cells.
- 2014
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Ingår i: Stem cells translational medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 3:12, s. 1484-94
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2(b)) mice were infused together with fully major histocompatibility complex-mismatched Balb/c (H2(d)) allogeneic islets into the portal vein of diabetic C57BL/6 (H2(b)) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3(+) regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naïve nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-γ production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3(+) regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine.
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