Rudolf Kunze

Immunoglobulin Adsorption in Patients With Idiopathic Dilated Cardiomyopathy

BACKGROUND Idiopathic dilated cardiomyopathy (IDC) frequently is a progressive disease without causative therapy options. Following the hypothesis that in certain patients autoantibodies against cardiac structures may induce, maintain, or promote the progression of the disease, we investigated whether the elimination of these autoantibodies through immunoadsorption would improve cardiac function. METHODS AND RESULTS This prospective case-control study included 34 patients with IDC. Each patient presented with moderate to severe heart failure and evidence of autoantibodies directed against beta(1)-adrenoceptors (beta(1)-AABs). Seventeen patients received standard medical therapy (control group), whereas 17 were also treated with immunoadsorption (treatment group) to eliminate beta(1)-AABs. A 1-year follow-up included echocardiographic assessment of left ventricular ejection fraction and internal diameters, beta(1)-AAB levels, and clinical status every 3 months. Within 1 year, the mean+/-SD left ventricular ejection fraction rose from 22.3+/-3.3% to 37.9+/-7.9% (P=0.0001) in the treatment group, with a relative increase of 69.9%. However, in the control group, no overall increase was seen (from 23.8+/-3.0% to 25.2+/-5.9%, P=0. 3154). Left ventricular diameter in diastole decreased by 14.5% from 74.5+/-7.1 to 63.7+/-6.0 mm in the treatment group (P=0.0001) and by 3.8% (P=0.2342) in the control group. In the treatment group, the NYHA functional rating improved after immunoadsorption (P=0.0001). beta(1)-AABs did not increase anew. CONCLUSIONS In IDC, the use of immunoadsorption is superior to the use of standard medical therapy. It significantly improves cardiac performance and clinical status.

Decreased oxidative stress in patients with idiopathic dilated cardiomyopathy one year after immunoglobulin adsorption

OBJECTIVES In a substudy to a recently reported investigation that demonstrated the benefit of immunoglobulin adsorption (immunoadsorption) for patients with idiopathic dilated cardiomyopathy (IDC), we tested whether this benefit is associated with a reduction of oxidative stress. BACKGROUND The progression of cardiomyopathy is believed to be related to the increase of oxidative stress. Therefore, reduction of oxidative stress could be one of the effects of immunoadsorption for improvement of cardiac performance and clinical status. METHODS Plasma markers for oxidative stress-thiobarbituric acid-reactive substances (TBARS), lipid peroxides (LPO), anti-oxidized low-density lipoprotein-autoantibodies (anti-oxLDL-AB), thiol groups and vitamin E-were compared in 31 patients, of whom 16 underwent immunoadsorption and 15 received conventional treatment (controls). All patients received a daily supplement of vitamins, minerals and trace elements. RESULTS After one year, TBARS (p = 0.026), LPO (p = 0.026) and anti-oxLD

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.

Antibodies to the α1-Adrenergic Receptor Cause Vascular Impairments in Rat Brain as Demonstrated by Magnetic Resonance Angiography

Background Circulating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the α1-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the α1-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments. Methodology/Principal Findings Using a rat model we studied the long-term action of antibodies against the α1-adrenergig receptor either induced by immunization with a receptor peptide or applied by intravenous injection. The vasculature in the rat brains was investigated by time-of-flight magnetic resonance angiography using a 9.4 Tesla small animal MR imaging system. Visual examination of maximum-intensity-projections (MIPs) of brain angiographs revealed the development of vascular defects in antibody- exposed animals between three and eight months of treatment. Relative vascular areas were derived from representative MIP image sections by grayscale analysis and used to form an index of vascular circulation. Animals exposed to the action of α1-adrenergig receptor antibodies showed significantly reduced vascular areas (p<0.05). Calculated index values indicated attenuated blood flow in both antibody-treated cohorts compared to their respective controls reaching with (relative units ± standard error, n = 10) 0.839±0.026 versus 0.919±0.026 statistical significance (p<0.05) for peptide-immunized rats. Conclusion/Significance We present evidence that antibodies to the α1-adrenergig receptor cause cerebrovascular impairments in the rat. Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of brain vasculature such as stroke and dementia.

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.

Immunoadsorption of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients with Mild to Moderate Dementia.

Dementia has been shown to be associated with agonistic autoantibodies. The deleterious action of autoantibodies on the α1‐adrenergic receptor for brain vasculature has been demonstrated in animal studies. In the current study, 169 patients with dementia were screened for the presence of agonistic autoantibodies. 47% of patients suffering from mild to moderate Alzheimers disease and/or vascular dementia carried these autoantibodies. Eight patients positive for autoantibodies underwent immunoadsorption. Patients treated on four consecutive days were subsequently negative for autoantibodies and displayed stabilization of cognitive and mental condition during 12–18 months’ follow‐up. In patients treated for 2–3 days, autoantibodies were reduced by only 78%. They suffered a rebound of autoantibodies during follow‐up, benefited from immunoadsorption too, but their mental parameters worsened. We provide first data on the clinical relevance of agonistic autoantibodies in dementia and show that immunoadsorption is safe and efficient in removing autoantibodies with overall benefits for patients.

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.

Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia

Over‐stimulation of G‐protein coupled receptors (GPCRs) such as α1‐adrenergic, muscarinic, endothelin, and AT1 receptors is considered to drive benign prostatic hyperplasia (BHP) which is often associated with lower urinary tract syndrome (LUTS). However, in addition to physiologic GPCR ligands, there is a new class of autoantibodies called functional autoantibodies that target the same GPCRs (GPCR‐AABs) for over‐stimulation, thus, presenting pathogenic potency. We hypothesize that patients with BPH/LUTS could carry GPCR‐AABs representing potential targets for treatment.

Removal of agonistic autoantibodies (agAAB) against adrenoceptors (AR) in patients with Alzheimer's disease / Alzheimer's disease with a vascular component (AD/VD)

P3-354 REMOVAL OFAGONISTIC AUTOANTIBODIES (AGAAB) AGAINSTADRENOCEPTORS (AR) IN PATIENTS WITH ALZHEIMER’S DISEASE / ALZHEIMER’S DISEASE WITH AVASCULAR COMPONENT (AD/VD) Elisabeth Steinhagen-Thiessen, Rudolf Kunze, Carola Jonatat, Ursula Kassner, Imke Decius, Peter Rosenthal, Petra Hempel, Peter Karczewski, Marion Bimmler, Charit e University Medicine Berlin, Berlin, Germany; Biomed Office, Berlin, Germany; Charite University Medicine Berlin, Berlin, Germany; Charit e, Berlin, Germany; Klinik L€udenscheid, Berlin, Germany; E.R.D.E. AAK-Diagnostik GmbH, Berlin, Germany; Erde, Berlin, Germany; MDC, Berlin, Germany.