C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation

Hecker, Jens; Lorenz, Ralf; Appiah, Richard; Vangerow, Burkhard; Loss, Martin; Kunz, Robert F.; Schmidtko, Jan; Mengel, Michael; Klempnauer, Jürgen; Piepenbrock, S.; Dickneite, Gerhard; Neidhardt, Helge; Rückoldt, H.; Winkler, Michael

doi:10.1097/00007890-200203150-00006

Cited by 30 publications

(18 citation statements)

References 30 publications

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“…In another study, the addition of C1 inhibitor did not further prolong the survival of ex vivo human blood perfused human CD55 transgenic pig lungs (Poling et al, 2006). In vivo , soluble C1 inhibitor suppressed hyperacute rejection and acute vascular rejection of kidneys in pig to cynomolgus monkey models (Hecker et al, 2002; Przemek et al, 2002; Vangerow et al, 2001). On the other hand, transplantation of pig hearts transgenic for either human DAF or MCP into baboons treated with C1 inhibitor resulted in efficient complement inhibition (Wu et al, 2007).…”

Section: C1 Inhibitor-mediated Modulation Of Inflammatory Diseasementioning

confidence: 99%

Biological activities of C1 inhibitor

Davis

Mejia

2008

Molecular Immunology

261

202

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Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.

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Section: C1 Inhibitor-mediated Modulation Of Inflammatory Diseasementioning

confidence: 99%

Biological activities of C1 inhibitor

Davis

Mejia

2008

Molecular Immunology

261

202

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“…Further, profound and prolonged inhibition of complement nonspecifically cripples a key component of the immune system, with predictable adverse consequences, i.e. bacterial septicemia [31]. Finally immunogenicity of CoVF limits its utility for long-term or repeated use in vivo [29].…”

Section: Regulation Of the Complement Cascadementioning

confidence: 99%

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Nguyen¹,

Zwets²,

Schroeder³

et al. 2005

CDTCHD

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The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

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“…1 Topographic scheme of the porcine and the human graft in situ. Arrows indicate direction of the blood flow and a short course of a supplemental C1-inhibitor (C1-Inh) [22,23].…”

Section: Animalsmentioning

confidence: 99%

Analysis of pig-to-human porcine endogenous retrovirus transmission in a triple-species kidney xenotransplantation model

Winkler¹,

Winkler

Burian³

et al. 2005

Transpl Int

Self Cite

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Clinical pig-to-human xenotransplantation might be associated with the risk of transmission of xenozoonoses, especially porcine endogenous retroviruses (PERVs). We have established a pig-to-humanised-cynomolgus monkey xenotransplantation model allowing the analysis of potential PERV-transmission from normal or transgenic porcine organs to human vascular tissue. Pig-to-human kidney xenotransplantation was performed in cynomolgus monkeys. An interposition graft constructed from a human saphena vein replaced the porcine kidney vein. After graft rejection and/or death of the recipient (survival 2, 4, 6, 13, 16, 19 days), the human interposition grafts were removed. Human endothelial cells (huECs) were isolated from the interposition grafts and cultivated in vitro. Explanted human vascular tissue, isolated huECs, plasma and serum samples of the graft recipients were characterised by flow cytometry and immunohistochemistry and screened for indications of PERV transmission by quantitative polymerase chain reaction (PCR), reverse transcriptase-polymerase chain reaction (RT-PCR) and RT assay. PERV-specific immune response of recipients was analysed by Western blot. No evidence of PERV infection or PERV-specific immune response was detected.

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C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation

Cited by 30 publications

References 30 publications

Biological activities of C1 inhibitor

Biological activities of C1 inhibitor

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Analysis of pig-to-human porcine endogenous retrovirus transmission in a triple-species kidney xenotransplantation model

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