Frank Gebauer

Peptide Based Adsorbers for Therapeutic Immunoadsorption

Abstract:  Peptides as ligands for immunoadsorption exhibit several potentialadvantages over native proteins. Two newly developed adsorbers arebased on peptides covalently coupled to sepharose CL‐4B. Globaffinis capable of binding immunoglobulins independent from their antigenspecificity and thus, applicable in transplant recipients and severalantibody mediated autoimmune diseases. Among others, the most importantdisorders suitable for the treatment with Globaffin are rheumatoidarthritis, systemic lupus erythematosus, and acute renal transplant rejection.Coraffin is a specific adsorber using two linear peptide ligandsmimicking epitopes of the β1‐adrenergic receptor,that bind corresponding autoantibodies from patients suffering fromidiopathic dilated cardiomyopathy. Specific immunoadsorption hasbeen shown to be beneficial for patients with dilated cardiomyopathy.Coraffin can be used as a new therapeutic option for these patients, who get only limited benefit from medicaltherapy. Both adsorbers may be combined with all approved apheresis control devices available.

Specific Removal of C-Reactive Protein by Apheresis in a Porcine Cardiac Infarction Model

Background: C-reactive protein (CRP) is a possible causative factor of the destructive processes observed during the weeks after myocardial infarction. Methods: We developed a clinically relevant animal model including the removal of CRP from blood plasma utilizing a specific CRP adsorber and the visualization of the infarct scar in the living animal by cardiovascular magnetic resonance imaging as a tool to investigate the impact of CRP after acute myocardial infarction. Results: We describe the facets of this model system and kinetics of clinical blood parameters like CRP and troponin. In addition, we demonstrate the potency of CRP apheresis reducing CRP levels by ∼70% in the established treatment system. Conclusion: We showed for the first time that it is possible to conduct apheresis at the following 2 days after acute myocardial infarction in a porcine infarction model and to analyze the infarct by cardiovascular magnetic resonance imaging at day 1 and 14.

Selective apheresis of C-reactive protein: A new therapeutic option in myocardial infarction?

Background: There is substantial evidence that C‐reactive protein (CRP) mediates secondary damage of the myocardium after acute myocardial infarction (AMI). The aim of this animal trial in pigs was to specifically deplete CRP from porcine plasma after AMI and to study possible beneficial effects of the reduced CRP concentration on the infarcted area. Methods: Ten pigs received balloon catheter‐induced myocardial infarction. CRP was depleted from five animals utilizing a new specific CRP‐adsorber, five animals served as controls. The area of infarction was analyzed by cardiovascular magnetic resonance imaging on day 1 and day 14 after AMI. Porcine CRP levels were determined by ELISA. Results: CRP‐apheresis resulted in a mean reduction of the CRP levels up to 48.3%. The area of infarction was significantly reduced by 30 ± 6% (P = 0.003) within 14 days in the treatment group, whereas it increased by 19 ± 11% (P = 0.260) in the controls. Fourteen days after infarction, the infarcted area revealed compact, transmural scars in the controls, whereas animals receiving CRP‐apheresis showed spotted scar morphology. In the interventional group, a significantly higher left ventricular ejection fraction (LVEF) was observed after 14 days as compared to the controls (57.6 ± 2.4% vs. 46.4 ± 2.7%; P = 0.007). Conclusions: In a pig model for AMI, we observed that selective CRP‐apheresis significantly reduces CRP levels and the volume of the infarction zone after AMI. Additionally, it changes the morphology of the scars and preserves cardiac output (LVEF). J. Clin. Apheresis 30:15–21, 2015.

Influence of Reduced Nicotinamide Adenine Dinucleotide on the Production of Interleukin-6 by Peripheral Human Blood Leukocytes

Objective: Recently, therapy with nicotinamide adenine dinucleotide (NADH) revealed positive effects on neurodegenerative disorders associated with inflammation of the CNS, such as Parkinson’s disease or Alzheimer’s disease. Pathophysiologically, focal CNS inflammation seems to be accompanied by an unbalanced cytokine production, pointing to an involvement of the immune system. Therefore, the aim of our study was to investigate whether NADH could influence cytokine release of peripheral blood leukocytes (PBLs) with special reference to interleukin-6 (IL-6). Methods: PBLs from 18 healthy donors were incubated in vitro with different concentrations of NADH to generate dose-response curves. As a control, mitogen-treated cells and unstimulated cells were included. Results: In PBLs from the 18 healthy donors, NADH significantly stimulated the dose-dependent release of IL-6, ranging from 6.25 to 400 µg/ml, compared to medium-treated cells (p < 0.001). An amount of 1,000 pg/ml IL-6 was induced by NADH concentrations ranging from 3.1 to >25 µg/ml. Conclusions: It is concluded that NADH possesses cytokine-modulating effects on peripheral blood cells. The biological relevance of these data is discussed in the context of the recent use of NADH for the treatment of several neurodegenerative disorders.

ELEVATION OF PLASMA COPEPTIN IN ACUTE MYOCARDIAL INFARCTION IN PIGS IS RELATED TO CHANGES IN MEAN ARTERIAL BLOOD PRESSURE BUT NOT TO MYOCARDIAL ISCHEMIA

Background: Copeptin increases early after myocardial infarction (MI). We used a porcine MI model with serial copeptin-testing and assessment of hemodynamic variables to evaluate the trigger for copetin-release and the liberation kinetics of copeptin in MI. Methods: AMI was induced by percutaneous transluminal coronary angioplasty (PTCA). Blood samples were taken in 30-minute intervals. Results: All animals (n=4) had a comparable infarction size (10.02 ± 2.11% of the left ventricle) and elevated troponin T levels. Highest copeptin levels were measured 30 minutes after the beginning of ischemia with a rapid decrease at 60 minutes, while coronary occlusion was still persisting. Animals with high copeptin values showed a significant drop of MAP (37.24% and 54.20% reduction from MAP-baseline). Conclusions: In experimental AMI in four pigs, the infarction-related decrease of MAP seemed to be the trigger for the copeptin increase. Remarkably, copeptin liberation was not correlated with infarction size and copeptin values already decreased while coronary artery occlusion was ongoing.