Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood

Jan-Michael Abicht; Ioannis Kourtzelis; Bruno Reichart; Sophia Koutsogiannaki; Alexandra Primikyri; John D Lambris; Triantafyllos Chavakis; Lesca Holdt; Alexander Kind; Sonja Guethoff; Tanja Mayr

doi:10.1111/xen.12262

Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood

Jan-Michael Abicht, Ioannis Kourtzelis, Bruno Reichart, Sophia Koutsogiannaki, Alexandra Primikyri, John D Lambris, Triantafyllos Chavakis, Lesca Holdt, Alexander Kind, Sonja Guethoff, Tanja Mayr

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3.

METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n=5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls.

RESULTS: Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 ± 0.34% vs 3.12 ± 0.48% control activation; P<.01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 ± 4.2 vs 3.5 ± 4.8 mL/min/g; P=.03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 ± 187 U/mL vs 2108 ± 1145 U/mL, P=.02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls.

CONCLUSIONS: Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild-type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.

Original language	English
Number of pages	11
Journal	XENOTRANSPLANTATION
Volume	24
Issue number	1
DOIs	https://doi.org/10.1111/xen.12262
Publication status	Published - 28 Feb 2017

Bibliographical note

Keywords

Animals
Complement Activation/immunology
Complement C3/metabolism
Graft Rejection/prevention & control
Heart
Heart Transplantation/methods
Humans
Myocardium/immunology
Pyridones/metabolism
Swine
Transplantation, Heterologous/methods

Access to Document

10.1111/xen.12262

Cite this

@article{ab94e6f7fadf44f2926363df49fe8e6c,

title = "Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood",

abstract = "BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3.METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n=5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls.RESULTS: Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 ± 0.34% vs 3.12 ± 0.48% control activation; P<.01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 ± 4.2 vs 3.5 ± 4.8 mL/min/g; P=.03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 ± 187 U/mL vs 2108 ± 1145 U/mL, P=.02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls.CONCLUSIONS: Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild-type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.",

keywords = "Animals, Complement Activation/immunology, Complement C3/metabolism, Graft Rejection/prevention & control, Heart, Heart Transplantation/methods, Humans, Myocardium/immunology, Pyridones/metabolism, Swine, Transplantation, Heterologous/methods",

author = "Jan-Michael Abicht and Ioannis Kourtzelis and Bruno Reichart and Sophia Koutsogiannaki and Alexandra Primikyri and Lambris, {John D} and Triantafyllos Chavakis and Lesca Holdt and Alexander Kind and Sonja Guethoff and Tanja Mayr",

note = "{\textcopyright} 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2017",

month = feb,

day = "28",

doi = "10.1111/xen.12262",

language = "English",

volume = "24",

journal = "XENOTRANSPLANTATION",

issn = "0908-665X",

publisher = "Wiley-Blackwell",

number = "1",

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TY - JOUR

T1 - Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood

AU - Abicht, Jan-Michael

AU - Kourtzelis, Ioannis

AU - Reichart, Bruno

AU - Koutsogiannaki, Sophia

AU - Primikyri, Alexandra

AU - Lambris, John D

AU - Chavakis, Triantafyllos

AU - Holdt, Lesca

AU - Kind, Alexander

AU - Guethoff, Sonja

AU - Mayr, Tanja

PY - 2017/2/28

Y1 - 2017/2/28

N2 - BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3.METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n=5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls.RESULTS: Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 ± 0.34% vs 3.12 ± 0.48% control activation; P<.01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 ± 4.2 vs 3.5 ± 4.8 mL/min/g; P=.03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 ± 187 U/mL vs 2108 ± 1145 U/mL, P=.02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls.CONCLUSIONS: Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild-type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.

AB - BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3.METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n=5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls.RESULTS: Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 ± 0.34% vs 3.12 ± 0.48% control activation; P<.01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 ± 4.2 vs 3.5 ± 4.8 mL/min/g; P=.03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 ± 187 U/mL vs 2108 ± 1145 U/mL, P=.02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls.CONCLUSIONS: Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild-type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.

KW - Animals

KW - Complement Activation/immunology

KW - Complement C3/metabolism

KW - Graft Rejection/prevention & control

KW - Heart

KW - Heart Transplantation/methods

KW - Humans

KW - Myocardium/immunology

KW - Pyridones/metabolism

KW - Swine

KW - Transplantation, Heterologous/methods

U2 - 10.1111/xen.12262

DO - 10.1111/xen.12262

M3 - Article

C2 - 27677785

SN - 0908-665X

VL - 24

JO - XENOTRANSPLANTATION

JF - XENOTRANSPLANTATION

IS - 1

ER -