Clinical Islet Xenotransplantation

Windt, Dirk J. van der; Bottino, Rita; Kumar, Gopal; Wijkstrom, Martin; Hara, Hidetaka; Ezzelarab, Mohamed; Ekser, Burçin; Phelps, Carol J.; Murase, Noriko; Casu, Anna; Ayares, David; Lakkis, Fadi G.; Trucco, Massimo; Cooper, David K.C.

doi:10.2337/db12-0033

Cited by 118 publications

(80 citation statements)

References 68 publications

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“…This preclinical goal, however, has been the subject of debate since it is hard to achieve in monkeys, raising the question of whether it is necessary before initiating a human clinical trial (7,8). Currently, several independent groups, including our own, have reported long-term survival of pig islets in diabetic NHPs (1,9,10), but insulin-independence for 6 months has been anecdotal, casting doubt on the translatability of this preclinical result to clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

Shin

Kim

et al. 2015

American Journal of Transplantation

173

194

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Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin-induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.

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Section: Introductionmentioning

confidence: 99%

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

Shin

Kim

et al. 2015

American Journal of Transplantation

173

194

View full text Add to dashboard Cite

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“…Color images available online at www.liebertpub.com/teb Nonetheless, islet transplantation remains an imperfect treatment due to limited long-term viability in vivo and the current need for a regiment of immunosuppressive drugs. 13 …”

Section: Figmentioning

confidence: 99%

Tissue Engineering Approaches to Cell-Based Type 1 Diabetes Therapy

Amer

Mahoney

Bryant

2014

Tissue Engineering Part B: Reviews

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Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of insulin-producing pancreatic b-cells. Cell-based therapies, involving the transplantation of functional b-cells into diabetic patients, have been explored as a potential long-term treatment for this condition; however, success is limited. A tissue engineering approach of culturing insulin-producing cells with extracellular matrix (ECM) molecules in threedimensional (3D) constructs has the potential to enhance the efficacy of cell-based therapies for diabetes. When cultured in 3D environments, insulin-producing cells are often more viable and secrete more insulin than those in two dimensions. The addition of ECM molecules to the culture environments, depending on the specific type of molecule, can further enhance the viability and insulin secretion. This review addresses the different cell sources that can be utilized as b-cell replacements, the essential ECM molecules for the survival of these cells, and the 3D culture techniques that have been used to benefit cell function.

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“…Xenotransplantation of porcine islets has been suggested as a new alternative for human islet transplantation (1); however, significant loss of islet cells during isolation and engraftment, immediate blood-mediated immune responses, and acute cellular rejection restrict its clinical applications (2)(3)(4). Consequently, it is important that islet viability is preserved and immune suppression is achieved for successful islet xenotransplantation.…”

Section: Introductionmentioning

confidence: 99%