Alginate Macroencapsulation of Pig Islets Allows Correction of Streptozotocin-Induced Diabetes in Primates up to 6 Months Without Immunosuppression

Dufrane, Denis; Goebbels, Rose-Marie; Gianello, Pierre

doi:10.1097/tp.0b013e3181f6e267

Cited by 218 publications

(191 citation statements)

References 24 publications

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“…Expression of B4GALNT2 in human cells significantly increased antibodydependent complement-mediated lysis when these cells were challenged with serum from pig-to-baboon cardiac xenotransplantation sensitized recipient serum [25] while its deletion in pig PBMCs efficiently reduced human IgG and IgM binding and decreased human anti-porcine cytotoxicity [26,27]. The fact that a strong humoral response was detected in nonhuman primates receiving alginate-encapsulated islets especially against αGal [28,29] further emphasizes the necessity to use GGTA1-KO pigs as a background for other genetic modifications. Instant blood-mediated inflammatory reaction (IBMIR) is initiated upon contact between host blood and xenografted tissue.…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 91%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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Purpose of Review Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. Recent Findings In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation. Moreover, combining multiple modifications is possible today thanks to new, improved genomic editing tools. Summary Genetic modification of large animals, pigs in particular, has come a long way during the last decade. These modifications can help minimize immunological and physiological incompatibilities between porcine and human cells, thus allowing for better tolerance and function of xenocells.

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Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 91%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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“…Lymphocytes and monocytes were nevertheless detected adjacent to the transplant site, and anti-porcine IgG levels were again strongly increased, suggesting encapsulation was unable to fully immunoisolate the xenograft. Furthermore, the fi ndings reinforced the similarity of immune-mediated rejection of encapsulate islets in both the primate and mouse/rat models [ 90 ].…”

Section: Understanding Xenograft Rejection In Nonhuman Primate Recipimentioning

confidence: 74%

“…Finally, the most recent of these studies showed that both microencapsulation and macroencapsulation devices could protect adult porcine islets from humoral rejection and T-cell mediated cytotoxicity, implanted in either the kidney capsule or peritoneal compartment of primates. The macroencapsulation device also corrected hyperglycemia in the NHP models for up to 6 months without immunosuppression [ 90 ]. Lymphocytes and monocytes were nevertheless detected adjacent to the transplant site, and anti-porcine IgG levels were again strongly increased, suggesting encapsulation was unable to fully immunoisolate the xenograft.…”

Section: Understanding Xenograft Rejection In Nonhuman Primate Recipimentioning

confidence: 90%

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Krishnan

Foster

et al. 2016

Methods in Molecular Biology

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Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of signifi cant parameters of bioencapsulation device design and manufacture (i.e., purifi cation protocols, surface-modifi cation grafting techniques, alginate composition modifi cations) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specifi c pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defi ning characteristics of the response itself.

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“…WT pig (e.g., DU, GLW, Landrace, and miniature) islet xenotransplantation has successfully reversed diabetes in primate models (Hering et al, 2006;Dufrane et al, 2010;Thompson et al, 2012). However, there is a significant loss of the transplanted cells on exposure to fresh recipient blood and heterologous antigen, known as instant blood-mediated inflammatory reaction (IBMIR), as well as subsequent humoral and T-cell response that results in xenorejection of islet grafts (Nilsson, 2008;Ekser and Cooper, 2010).…”

Section: Genetically Engineered Pig: An Alternative Selection Of Islementioning

confidence: 99%

“…At present, only islet xenografts isolated from neonatal (2-3 d) and adult pigs (>6 months) display the ability to reverse diabetes in non-human primates (NHPs) or humans (Hering et al, 2006;Elliott et al, 2007;Dufrane et al, 2010;Thompson et al, 2012).…”

Section: Optimum Age Of Donor Pigmentioning

confidence: 99%

异种胰岛移植中供体猪的筛选: 现状与进展

Zhu

Lyu

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Islet transplantation is an attractive treatment of type 1 diabetes mellitus. Xenotransplantation, using the pig as a donor, offers the possibility of an unlimited supply of islet grafts. Published studies demonstrated that pig islets could function in diabetic primates for a long time (>6 months). However, pig-islet xenotransplantation must overcome the selection of an optimal pig donor to obtain an adequate supply of islets with high-quality, to reduce xenoantigenicity of islet and prolong xenograft survival, and to translate experimental findings into clinical application. This review discusses the suitable pig donor for islet xenotransplantation in terms of pig age, strain, structure/function of islet, and genetically modified pig.

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Alginate Macroencapsulation of Pig Islets Allows Correction of Streptozotocin-Induced Diabetes in Primates up to 6 Months Without Immunosuppression

Abstract: Pig islets encapsulated in a subcutaneous macrodevice can control diabetes up to 6 months without immunosuppression.

Cited by 218 publications

References 24 publications

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

异种胰岛移植中供体猪的筛选: 现状与进展

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