In vivo inhibition of neutrophil activity by a FAS (CD95) stimulating module: arterial in-line application in a porcine cardiac surgery model

Scholz, Martin; Simon, A; Berg, M M Van den; Schüller, Alina; Hacibayramoglu, Meltem; Margraf, Stefan; Theisen, A.; Windolf, Joachim; Wimmer‐Greinecker, Gerhard; Moritz, Anton

doi:10.1016/j.jtcvs.2003.09.027

Cited by 20 publications

(22 citation statements)

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“…The ability of the mouse-anti-human agonistic anti-Fas IgM used in this study to induce porcine neutrophil apoptosis and to impair the effector functions was shown in earlier studies [22,25]. In previous experiments and in experiments that were done to establish this model, mini circuits without antibody coating were run to exclude effects mediated by the circuit itself.…”

Section: Discussionmentioning

confidence: 97%

“…The proof of concept of such an approach had been previously shown in patients undergoing cardiac surgery [24,25]. …”

Section: Discussionmentioning

confidence: 99%

“…Recently, we developed an extracorporeal immune therapy approach to inactivate circulating neutrophils by targeting neutrophil Fas [22-25]. It is known that adequate cross-linking of Fas (APO-1, CD95) on the neutrophil surface membrane stimulates proapoptotic signaling pathways [26,27] but probably may also lead to cellular changes independent from apoptosis [28].…”

Section: Introductionmentioning

confidence: 99%

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Extracorporeal immune therapy with immobilized agonistic anti-Fas antibodies leads to transient reduction of circulating neutrophil numbers and limits tissue damage after hemorrhagic shock/resuscitation in a porcine model

Lögters

Altrichter

Paunel-Görgülü

et al. 2010

Journal of Inflammation

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BackgroundHemorrhagic shock/resuscitation is associated with aberrant neutrophil activation and organ failure. This experimental porcine study was done to evaluate the effects of Fas-directed extracorporeal immune therapy with a leukocyte inhibition module (LIM) on hemodynamics, neutrophil tissue infiltration, and tissue damage after hemorrhagic shock/resuscitation.MethodsIn a prospective controlled double-armed animal trial 24 Munich Mini Pigs (30.3 ± 3.3 kg) were rapidly haemorrhaged to reach a mean arterial pressure (MAP) of 35 ± 5 mmHg, maintained hypotensive for 45 minutes, and then were resuscitated with Ringer' solution to baseline MAP. With beginning of resuscitation 12 pigs underwent extracorporeal immune therapy for 3 hours (LIM group) and 12 pigs were resuscitated according to standard medical care (SMC). Haemodynamics, haematologic, metabolic, and organ specific damage parameters were monitored. Neutrophil infiltration was analyzed histologically after 48 and 72 hours. Lipid peroxidation and apoptosis were specifically determined in lung, bowel, and liver.ResultsIn the LIM group, neutrophil counts were reduced versus SMC during extracorporeal immune therapy. After 72 hours, the haemodynamic parameters MAP and cardiac output (CO) were significantly better in the LIM group. Histological analyses showed reduction of shock-related neutrophil tissue infiltration in the LIM group, especially in the lungs. Lower amounts of apoptotic cells and lipid peroxidation were found in organs after LIM treatment.ConclusionsTransient Fas-directed extracorporeal immune therapy may protect from posthemorrhagic neutrophil tissue infiltration and tissue damage.

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Section: Discussionmentioning

confidence: 97%

“…The proof of concept of such an approach had been previously shown in patients undergoing cardiac surgery [24,25]. …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extracorporeal immune therapy with immobilized agonistic anti-Fas antibodies leads to transient reduction of circulating neutrophil numbers and limits tissue damage after hemorrhagic shock/resuscitation in a porcine model

Lögters

Altrichter

Paunel-Görgülü

et al. 2010

Journal of Inflammation

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“…When compared to the TUNEL assay, both methods have shown a similar sensitivity and specificity [15]. Scholz and Leaes have recently employed annexin V technique for the analysis of neutrophil and lymphoid apoptosis that occurred during CPB in pigs and humans, respectively [11,12]. Annexin V staining reveal phosphatidylserine outer leaflet membrane exposure, which is one of the earliest hallmarks of cells undergoing apoptosis [1,15,23,24].…”

Section: Discussionmentioning

confidence: 99%

Influence of hypothermia on right atrial cardiomyocyte apoptosis in patients undergoing aortic valve replacement

Castedo

Castejón

Monguió

et al. 2007

J Cardiothorac Surg

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BackgroundThere is increasing evidence that programmed cell death can be triggered during cardiopulmonary bypass (CPB) and may be involved in postoperative complications. The purpose of this study was to investigate whether apoptosis occurs during aortic valve surgery and whether modifying temperature during CPB has any influence on cardiomyocyte apoptotic death rate.Methods20 patients undergoing elective aortic valve replacement for aortic stenosis were randomly assigned to either moderate hypothermic (ModHT group, n = 10, 28°C) or mild hypothermic (MiHT group, n = 10, 34°C) CPB. Myocardial samples were obtained from the right atrium before and after weaning from CPB. Specimens were examined for apoptosis by flow cytometry analysis of annexin V-propidium iodide (PI) and Fas death receptor staining.ResultsIn the ModHT group, non apoptotic non necrotic cells (annexin negative, PI negative) decreased after CPB, while early apoptotic (annexin positive, PI negative) and late apoptotic or necrotic (PI positive) cells increased. In contrast, no change in the different cell populations was observed over time in the MiHT group. Fas expression rose after reperfusion in the ModHT group but not in MiHT patients, in which there was even a trend for a lower Fas staining after CPB (p = 0.08). In ModHT patients, a prolonged ischemic time tended to induce a higher increase of Fas (p = 0.061).ConclusionOur data suggest that apoptosis signal cascade is activated at early stages during aortic valve replacement under ModHT CPB. This apoptosis induction can effectively be attenuated by a more normothermic procedure.

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“…Cheung and Anseth [16] previously demonstrated that DX2 induces nearly 20% T cell apoptosis when covalently conjugated to the surface of gels formed from 7.5 wt% PEGDA and 2.5 wt% N-hydroxysucinimide-PEG-acrylate (NPA) hydrogel. Others have shown a local anti-inflammatory effect mediated by IgM-class anti-Fas antibodies adsorbed to polyester membranes [22,23]. While coating anti-Fas antibody directly onto biomaterial surfaces preserves some biological activity, these strategies yield a relatively low protein surface density and limited accessibility of functional groups to the surroundings.…”

Section: Introductionmentioning

confidence: 99%

Inducing local T cell apoptosis with anti-Fas-functionalized polymeric coatings fabricated via surface-initiated photopolymerizations

Hume

Anseth

2010

Biomaterials

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Cell encapsulation has long been investigated as a means to achieve transplant immunoprotection as it creates a physical barrier between allograft tissue and host immune cells. Encapsulation with passive barrier materials alone, however, is generally insufficient to protect donor tissue from rejection, because small cytotoxic molecules produced by activated T cells can diffuse readily into the capsule and mediate allograft death. As a means to provide bioactive protection for polymeric encapsulation devices, we investigated a functionalized polymeric coating that mimics a natural T cell regulation pathway. T cells are regulated in vivo via Fas, a well-known 'death receptor,' whereby effector cells express Fas ligand and elicit T cell apoptosis upon binding the Fas receptor on a T cell surface. Anti-Fas antibodies are capable of replicating this effect and induce T cell apoptosis in solution. Here, an iniferter-based living radical polymerization was utilized to fabricate surfaceanchored polymer chains containing poly(ethylene glycol) with covalently-incorporated pendant anti-Fas antibody. Using this reaction mechanism, we demonstrate fabrication conditions that yield surface densities in excess of 1.5 ng/cm 2 of incorporated therapeutic, as detected by ELISA. Additionally, we show that coatings containing anti-Fas antibody induced significant T cell apoptosis, 21±2 % of cells, after 24 hours. Finally, the incorporation of a T cell adhesion ligand, intracellular adhesion molecule-1, along with anti-Fas antibody, yielded even higher levels of apoptosis, 34±1% of T cells, compared to either signal alone.

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In vivo inhibition of neutrophil activity by a FAS (CD95) stimulating module: arterial in-line application in a porcine cardiac surgery model

Abstract: The leukocyte inhibition module downregulated cardiopulmonary bypass-related neutrophil activity and thus might be beneficial in cardiac surgery and other clinical settings with unappreciated neutrophil activation.

Cited by 20 publications

References 30 publications

Extracorporeal immune therapy with immobilized agonistic anti-Fas antibodies leads to transient reduction of circulating neutrophil numbers and limits tissue damage after hemorrhagic shock/resuscitation in a porcine model

Extracorporeal immune therapy with immobilized agonistic anti-Fas antibodies leads to transient reduction of circulating neutrophil numbers and limits tissue damage after hemorrhagic shock/resuscitation in a porcine model

Influence of hypothermia on right atrial cardiomyocyte apoptosis in patients undergoing aortic valve replacement

Inducing local T cell apoptosis with anti-Fas-functionalized polymeric coatings fabricated via surface-initiated photopolymerizations

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