The Role of the Alternative Complement Pathway in Early Graft Loss After Intraportal Porcine Islet Xenotransplantation

Kang, Hee Jung; Lee, Haneulnari; Ha, Joo Young; Lee, Jae‐Il; Shin, Jong Son; Kim, Ki-Yong; Park, Ji Yoon; Kim, Jung-Sik; Min, Sang Il; Park, Chung Gyu; Park, Seong Hoe; Kim, Sang Joon

doi:10.1097/tp.0000000000000069

Cited by 31 publications

(49 citation statements)

References 34 publications

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“…Very recently, a humanized CVF has been developed and confirmed its activity in a preclinical model without toxicity or immunogenicity (37). Moreover, we found that, upon intraportal infusion, adult pig islets activated the alternative pathway of the complement system, and that purified human factor H effectively prevented early islet loss as revealed by preservation of porcine C-peptide and reduced complement C3a and factor Bb (16). Therefore, we anticipate that successful replacement of anti-CD154 monoclonal antibody and introduction of purified human factor H or humanized CVF will allow us to replicate the results of this study in another set of monkey experiments and to begin clinical trials of pig islet transplantation in T1D patients.…”

Section: Discussionmentioning

confidence: 77%

“…R080, R084, and R089 monkeys were insulin-independent for 168, 303, and 180 days, respectively. Blood glucose data for R080 and, R084 were partly presented under the identities of R10 and R11, respectively, in our recent study (for another purpose) (16). Absence of monkey C-peptide measured at intervals indicated that blood glucose control was entirely dependent on porcine C-peptide from the transplanted pig islets, but not on endogenous beta cell regeneration.…”

Section: Cd8mentioning

confidence: 99%

“…The plasma concentrations of anti-Gal IgG were determined weekly using an enzyme-linked immunosorbent assay (ELISA) as previously described (16).…”

Section: Measurement Of Anti-gal Igg Levelsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 77%

Section: Cd8mentioning

confidence: 99%

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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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“…20 Although the use of MSCs has been accepted as one of the therapeutic approaches like other therapeutic cell therapies including pancreatic islets and hepatocyte and a number of successful reports have been published, the biocompatibility of MSC as well as of the other therapeutic cells still remain to be improved. Although systemic administration of anticoagulants and certain complement inhibitors are efficient in protecting the cells from thromboinflammation, [25][26][27][28][29] this treatment will increase the risk of bleeding in the patients. We have earlier reported that the expression of tissue factor on the cell surface triggers thromboinflammation, resulting in an early loss of the transplanted cells.…”

Section: Discussionmentioning

confidence: 99%

Modification of human MSC surface with oligopeptide‐PEG‐lipids for selective binding to activated endothelium

Noiri

Asawa

Okada

et al. 2019

J Biomedical Materials Res

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Promising cell therapies using mesenchymal stem cells (MSCs) is proposed for stroke patients. Therefore, we aimed to efficiently accumulate human MSC (hMSC) to damaged brain area to improve the therapeutic effect using poly(ethylene glycol) (PEG)‐conjugated phospholipid (PEG‐lipid) carrying an oligopeptide as a ligand, specific for E‐selectin which is upregulated on activated endothelial cells under hypoxia‐like stroke. Here we synthesized E‐selectin‐binding oligopeptide (ES‐bp) conjugated with PEG spacer having different molecular weights from 1 to 40 kDa. We found that ES‐bp can be immobilized onto the hMSC surface through PEG‐lipid without influence on cell growth and differentiation into adipocytes and osteocytes, respectively. It is also possible to control the immobilization of ES‐bp on hMSC surface (<108 ES‐bp per cell). Immobilized ES‐bp can be continuously immobilized at the outside of cell membrane when PEG‐lipids with PEG 5 and 40 kDa were used. In addition, the modified hMSC can specifically attach onto E‐selectin‐immobilized surface as a model surface of activated endothelium in human blood, indicating the sufficient number of immobilized ES‐bp onto hMSC. Thus, this technique is one of the candidates for hMSC accumulation to cerebral infarction area. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1779–1792, 2019.

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“…Strong complement activation has been observed during IBMIR [54]. In particular, activation of alternative complement pathway was profound in pig-to-NHP islet transplantation [55]. Following immediate responses by soluble inflammatory mediators, infiltration of islet grafts by large numbers of activated CD11b + neutrophils and macrophage was observed [56].…”

Section: Monitoring Of Cell-mediated Immune Responsesmentioning

confidence: 92%

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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The Role of the Alternative Complement Pathway in Early Graft Loss After Intraportal Porcine Islet Xenotransplantation

Abstract: The alternative complement pathway contributes to the development of IBMIR and the early loss of grafts in NHPs with porcine ITx. Complement inhibition during the peritransplant period may be beneficial for the survival of islet grafts.

Cited by 31 publications

References 34 publications

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

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

Modification of human MSC surface with oligopeptide‐PEG‐lipids for selective binding to activated endothelium

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

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