Porcine complement regulators protect aortic smooth muscle cells poorly against human complement‐induced lysis and proliferation: consequences for xenotransplantation

Capey, Steven; Berg, Carmen W. van den

doi:10.1111/j.1399-3089.2005.00217.x

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…(33–37) Interestingly, our experiments demonstrated increased C4d deposition on AIs compared to GTKO NPIs, although there were no differences in C1q, C3d, or IgG staining between AIs and GTKO NPIs. Thus, we are not able to point towards a classical or alternative pathway for the activation of C4 complement.…”

Section: Discussionmentioning

confidence: 62%

Early barriers to neonatal porcine islet engraftment in a dual transplant model

Samy

Davis

Gao

et al. 2018

American Journal of Transplantation

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Porcine islet xenografts have the potential to provide an inexhaustible source of islets for β cell replacement. Proof-of-concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including the poorly understood instant blood-mediated inflammatory reaction and a thorough understanding of early xeno-specific immune responses. A paucity of data exist comparing xeno-specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling])-positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (wild-type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3-galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.

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Section: Discussionmentioning

confidence: 62%

Early barriers to neonatal porcine islet engraftment in a dual transplant model

Samy

Davis

Gao

et al. 2018

American Journal of Transplantation

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“…Specifically, porcine tissue has been shown to be particularly susceptible to complement-mediated destruction due to lack of human complement regulatory factors (57). Complement activation was clearly noted in both the WT and GTKO NPIs.…”

Section: Discussionmentioning

confidence: 99%

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

Martin

Samy

et al. 2015

American Journal of Transplantation

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Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. Wild-type (WT) and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets (NPIs) were studied in non-immunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at one and 24 hours after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages, and platelets. Insulin, complement, antibody, neutrophils, macrophages, and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 hours in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

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“…Expression of DAF, which is sensitive to trypsin (22), was assessed by ELISA. ECs were incubated with 20 ng/ml IL-4 in 1% FBS/DMEM for 48 h in triplicate wells, washed twice with RPMI 1640 medium, and incubated with 15% human serum in RPMI 1640 medium for complement studies.…”

Section: Complement Regulators and Complement Activationmentioning

confidence: 99%

Porcine Endothelial Cells and Iliac Arteries Transduced with AdenoIL-4 Are Intrinsically Protected, through Akt Activation, against Immediate Injury Caused by Human Complement

Black¹,

Grehan²,

Rivard³

et al. 2006

The Journal of Immunology

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Vascular endothelial cells (ECs) can be injured in a variety of pathologic processes that involve activated complement. We reported previously that porcine ECs incubated with exogenous IL-4 or IL-13 are protected from cytotoxicity by human complement and also from apoptosis by TNF-α. The resistance to complement consists of an intrinsic mechanism that is lost a few days after cytokine removal. In our current study, we investigated whether transfer of the IL-4 gene into porcine ECs in vitro and into porcine vascular tissues in vivo would induce efficient and durable protection from human complement. We found that ECs transduced with adenoIL-4 or adenoIL-13 exhibited continuous production of the cytokine and prolonged protection from complement-mediated killing. IL-4 also protected ECs from activation: ECs incubated with IL-4 did not develop cell retraction and intercellular gaps upon stimulation with sublytic complement. The endothelium and subendothelium of pig iliac arteries that were transduced with the IL-4 gene were effectively protected from complement-dependent immediate injury after perfusion with human blood. However, after similar perfusion, the endothelium was immediately lost from arteries that were transduced with a control adenovirus. The protection was not due to up-regulation of the complement regulators decay accelerating factor, membrane cofactor protein, and CD59, or to reduced complement activation, but required the participation of Akt. Although our studies model protection in pig-to-primate xenotransplantation, our findings of IL-4 induction of Akt-mediated protection may be more broadly applicable to EC injury as manifested in ischemia-reperfusion, allotransplantation, and various vascular diseases.

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Porcine complement regulators protect aortic smooth muscle cells poorly against human complement‐induced lysis and proliferation: consequences for xenotransplantation

Cited by 10 publications

References 34 publications

Early barriers to neonatal porcine islet engraftment in a dual transplant model

Early barriers to neonatal porcine islet engraftment in a dual transplant model

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

Porcine Endothelial Cells and Iliac Arteries Transduced with AdenoIL-4 Are Intrinsically Protected, through Akt Activation, against Immediate Injury Caused by Human Complement

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