Failure of transplantation tolerance induction by autologous regulatory T cells in the pig‐to‐non‐human primate islet xenotransplantation model

Shin, Juyeon; Min, Bon Hong; Kim, Jong Min; Kim, Jung-Sik; Yoon, Ina; Kim, Hyun Je; Kim, Yong Hee; Jang, Jae Yool; Kang, Hee Jung; Lim, Dhongil; Ha, Jongwon; Kim, Sang Joon; Park, Chung Gyu

doi:10.1111/xen.12246

Cited by 53 publications

(66 citation statements)

References 12 publications

(17 reference statements)

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“…Although several independent research groups have shown long‐term porcine islet graft survival in diabetic NHPs for longer than 6 months, the results were rather anecdotal and unsatisfactory to meet the success criteria of the IXA consensus statement . In 2015, Shin and Park et al first reported the consistent long‐term porcine islet graft survival for longer than 6 months in 5 consecutive diabetic animals (Figure ) with an anti‐CD154 monoclonal antibody (mAb)‐based immunosuppression regimen, with the longest survival reaching 965 days post‐transplantation (Figure ) . As anti‐CD154 mAbs have been known to cause thromboembolic complications, an anti‐CD154 sparing regimen needs to be developed for the clinical application.…”

Section: Research Activities In Xenotransplantationmentioning

confidence: 99%

Current status of xenotransplantation in South Korea

Park

Shin

Min

et al. 2019

Xenotransplantation

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Section: Research Activities In Xenotransplantationmentioning

confidence: 99%

Current status of xenotransplantation in South Korea

Park

Shin

Min

et al. 2019

Xenotransplantation

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“…These data are consistent with reports by Korsgren and colleagues which indicated that even a small number of T cells is sufficient to initiate rejection of porcine islets by macrophages in T-cell-deficient rodents (29). More recently, Shin et al reported that pig islets, engrafted >500 days in non-human primates, were fully rejected by activated immune cells, particularly CD4+ and CD8+ T cells, when immunosuppressive maintenance drugs were discontinued (12). Therefore, strategies directed at inhibition of the direct and indirect pathways must be included for successful xenotransplantation between pigs and primates.…”

Section: Tolerance-inducing Strategies Across Xenogeneic Immunolomentioning

confidence: 99%

“…The recipients eventually died from infection associated with chronic immunosuppression or from graft rejection (3, 4, 10, 11). Attempts to taper immunosuppression have been unsuccessful (12). These data are consistent with previous reports (13, 14) indicating that the human-anti-porcine T-cell response is similar or stronger than that across allogeneic barriers.…”

Section: Introductionmentioning

confidence: 99%

Tolerance in xenotransplantation

Yamada

Sykes²,

Sachs³

2017

Current Opinion in Organ Transplantation

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This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation. Recent findings Using advanced gene editing technologies, xenotransplantation from multi-transgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and >2 years in a heterotopic non-life-supporting cardiac xenograft model. Continuous administration of multiple immunosuppressive drugs has been required and attempts to taper immunosuppression have been unsuccessful. It appears likely that low levels of T cell-dependent antibodies and activation of innate responses are responsible for xenograft loss. Mixed chimerism and thymic transplantation approaches have achieved xenogeneic tolerance in pig-to-mouse models and both have recently been extended to pig-to-baboon models. Encouraging results have been reported, including persistence of macrochimerism, prolonged pig skin graft survival, donor-specific unresponsiveness in vitro and detection of recent T cell emigrants in vivo. Summary Although tolerance induction in vivo has not yet been achieved in pig-to-baboon models, recent results are encouraging that this goal will be attainable through genetic engineering of porcine donors.

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“…Recently, our group reported successful results where five consecutive diabetic monkeys achieved normoglycemia for at least 6 months after transplantation of adult porcine islets, with the longest survival day reaching to >603 days [26]. During a follow-up study, one monkey showed normoglycemia up to ~1000 days using a CD40-CD154 blockade such as anti-CD154 or anti-CD40 monoclonal antibody [27]. These two studies pose an important implication that porcine islet graft can survive in the liver, which is rather a harsh environment, for a significantly long duration.…”

Section: Introductionmentioning

confidence: 99%

Pig-to-Nonhuman Primate (NHP) Naked Islet Xenotransplantation

Shin¹,

Kim²,

Min³

et al. 2017

Xenotransplantation - New Insights

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Islet transplantation is an established therapy for selected type 1 diabetes (T1D) patients with severe hypoglycemic unawareness and glycemic liability despite of insulin treatment. However, the donor organ is limited. Porcine islets are the best alternative source to overcome this limitation, and pig-to-nonhuman primate (NHP) naked islet xenotransplantation studies are being performed worldwide. Several studies including our own have presented successful proof-of-concept results based on immunosuppression regimen including the anti-CD154 monoclonal antibody. Particularly, long-term control of diabetes by adult porcine islet transplantation has been demonstrated in five consecutive monkeys, and the longest survival was ~1000 days after transplantation. Currently, pig-to-NHP islet xenotransplantation based on clinically applicable immunosuppression regimen is being pursued. In this chapter, we will describe all the procedures of pigto-NHP naked islet xenotransplantation: (1) the porcine islet isolation from designated pathogen-free (DPF) miniature pigs, (2) diabetes induction in monkeys, (3) transplantation procedure via the portal vein, (4) immune monitoring comprising humoral and cellular immunity after porcine islet transplantation, and finally (5) liver biopsy and subsequent immunohistochemical procedure in detail.

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Failure of transplantation tolerance induction by autologous regulatory T cells in the pig‐to‐non‐human primate islet xenotransplantation model

Abstract: Taken together, autologous Tregs infused at the peri-transplantation period failed to induce transplantation tolerance in pig-to-NHP islet xenotransplantation setting.

Cited by 53 publications

References 12 publications

Current status of xenotransplantation in South Korea

Current status of xenotransplantation in South Korea

Tolerance in xenotransplantation

Pig-to-Nonhuman Primate (NHP) Naked Islet Xenotransplantation

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