Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates

Wijkstrom, Martin; Kirchhof, Nicole; Graham, Melanie L.; Ingulli, Elizabeth; Colvin, Robert B.; Christians, Uwe; Hering, Bernhard J.; Schuurman, Henk Jan

doi:10.1016/j.tox.2004.09.010

Cited by 27 publications

(21 citation statements)

References 16 publications

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“…This has been observed in the case of STZ where mild injury to the kidney can increase vulnerability to toxic insult later during therapeutic intervention using a compound with nephrotoxic adverse side effects (Wijkstrom et al, 2005).…”

Section: Divergence Between the Model And The Human Individual In Thementioning

confidence: 96%

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

Graham

Schuurman²

2015

European Journal of Pharmacology

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Section: Divergence Between the Model And The Human Individual In Thementioning

confidence: 96%

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

Graham

Schuurman²

2015

European Journal of Pharmacology

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“…(6) Exogenous insulin is administrated to maintain BG level < 300 mg/dL (maximum) in diabetic monkeys before transplant and following islet graft rejection [82–86]. (7) Since cyclosporine can facilitate renal dysfunction in STZ-induced diabetic monkeys [87], an intensive and careful adverse event monitoring (AEM) should be conducted as soon as immunosuppressive treatment starts in the islet transplant recipients.…”

Section: Induction Of Dm In Nhps For Islet Transplantationmentioning

confidence: 99%

“…Administration of a low-dose STZ (20–50 mg/kg body weight) was not sufficient and reliable to consistently induce complete DM (C-P negative DM) in cynomolgus monkeys [89, 90]. Higher doses of STZ (80–150 mg/kg body weight) were found to be effective and sufficient [13, 81, 84, 87, 91–93] but were associated with more systemic side effects (e.g., transient vomiting, severe hypoglycemia) and serious complications (e.g., hepatic and renal function/tissue injury), as well as higher morbidity and mortality (approximately 28.6%–100%) [69, 87, 92–94]. Koulmanda et al [78], Tal et al [95], Dufrane et al [94], and Zou et al [96] demonstrated that STZ dose of 50–70 mg/kg could induce stable IDDM in all macaques for up to 0.5–1 y without any evidence of regeneration of β -cell, as well as liver and kidney toxicity.…”

Section: Induction Of Dm In Nhps For Islet Transplantationmentioning

confidence: 99%

“…On the contrary, Theriault and colleagues reported the safe and consistent induction of IDDM with a single high-dose of STZ (150 mg/kg body weight) in young cynomolgus monkeys (6–8-month-old). Moreover, Wijkstrom et al [87] recommended that the STZ dose should depend on body surface area (BSA) (1250 mg/m 2 ) rather than body weight (BW). Zou et al [96] further demonstrated that a dose > 760 mg/m 2 of STZ might reliably induce IDDM in juvenile cynomolgus monkeys (2-3-year-old), whereas a dose < 700 mg/m 2 was not effective.…”

Section: Induction Of Dm In Nhps For Islet Transplantationmentioning

confidence: 99%

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Nonhuman Primate Models of Type 1 Diabetes Mellitus for Islet Transplantation

Zhu

et al. 2014

Journal of Diabetes Research

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Islet transplantation is an attractive treatment of type 1 diabetes mellitus (T1DM). Animal models of diabetes mellitus (DM) contribute a lot to the experimental studies of islet transplantation and to evaluations of isolated islet grafts for future clinical applications. Diabetic nonhuman primates (NHPs) represent the suitable models of DMs to better evaluate the effectiveness of islet transplantation, to assess new strategies for controlling blood glucose (BG), relieving immune rejection, or prolonging islet survival, and eventually to translate the preclinical data into tangible clinical practice. This review introduces some NHP models of DM, clarifies why and how the models should be used, and elucidates the usefulness and limitations of the models in islet transplantation.

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“…Primary non-function may be attributed to transplantation of islets of poor quality (43). Other factors can involve autoimmunity (18,50,59), rejection (48), immunosuppression toxicity (31,36,58), and post-transplant inflammatory conditions (22). Significant attention has been directed toward the development of strategies to improve organ retrieval and islet isolation (2,16,19,20) and although both have been improved over time, protocols and products are not completely standardized.…”

Section: Introductionmentioning

confidence: 99%

Impact of Islet Size on Pancreatic Islet Transplantation and Potential Interventions to Improve Outcome

et al. 2015

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Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation from 30 to 60% of the islets is lost. In our study, we have investigated: 1) the role of size as a factor affecting islet engraftment and, 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 µm; medium 150–300 µm; small, ρ50 µm). Each size was transplanted in chemically induced diabetic mice as full (600 IEq), suboptimal (400 IEq), and marginal mass (200 IEq). Control animals received all size islets. Engraftment was defined as reversal of diabetes by day 7 post-transplantation. When the superiority of smaller islets was observed, strategies of over-digestion and fragmentation were adopted during islet isolation in the attempt to reduce islet size and improve engraftment. Smaller islets were significantly superior in engraftment as compared to medium, large, and control (all sizes) groups. This was more evident when marginal mass data were compared. In all masses, success decreased as islet sizes increased. Once islets were engrafted, functionality was not affected by size. When larger islets were fragmented, a significant decrease in islet functionality was observed. On the contrary, if pancreata were slightly over-digested, although not as successful as small naive islets, an increase in engraftment was observed when compared to the control group. In conclusion, smaller islets are superior in engraftment following islet transplantation. Fragmentation has a deleterious effect on islet engraftment. Islet isolations can be performed reducing islet size with slight over-digestion and it can be safely adopted to improve clinical outcome.

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Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates

Cited by 27 publications

References 16 publications

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

Nonhuman Primate Models of Type 1 Diabetes Mellitus for Islet Transplantation

Impact of Islet Size on Pancreatic Islet Transplantation and Potential Interventions to Improve Outcome

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