title: Treatment of humoral rejection after heart transplantation.
abstract: BACKGROUND
  Until a few years ago, the incidence of humoral rejection after heart transplantation was underestimated. These episodes were frequently very aggressive and often fatal, because the maintenance and emergency immunosuppression available at the time only inadequately covered the humoral branch of the immune response. In spite of individual case reports, the effects of blood purification procedures or cyclophosphamide in this situation can only be insufficiently estimated.
  
  
  METHODS
  To evaluate this therapy concept, 20 dog-lymphocyte-antigen-matched dogs underwent heterotopic neck-heart transplantation. Fourteen dogs underwent transplantation after having been previously sensitized through multiple skin transplantations, 6 dogs were not sensitized (control). The animals received an induction with 3x 250 mg prednisolone, as well as triple immunosuppression (cyclosporine, azathioprine, and cortisone). Biopsy (light microscopy, immunofluorescence), intramyocardial voltage, electric myocardial impedance (>200 kHz, <10 kHz), and echocardiographic (left ventricular wall thickness, diastolic relaxation velocity) examinations were performed daily to monitor rejection. Rejection therapy was continued for 3 days according to the following regimen: apheresis, cortisone boluses (CB), and cyclophosphamide in group A1 (n = 4), apheresis and CB without cyclophosphamide in group A2 (n = 4), and CB only in group C (n = 6). The subsequent course under triple immunosuppression was then observed.
  
  
  RESULTS
  In the sensitized animals the onset of severe humoral rejection on the fifth day deteriorated cardiac function down to 75% (70% to 80%) of the initial values. In groups A1 and A2, apheresis resulted in recovery to near-control values (89% to 94%) within two hours, and indeed to complete recovery (97% to 101%) after the second apheresis, that is, within 1 day. In group C recovery was delayed (2 days) and incomplete (84% to 91 %). After therapy was discontinued, rejection-related functional deterioration recurred immediately in group C, and from 2 to 3 days after apheresis, regardless of whether cyclophosphamide therapy was performed (group A1) or not (group A2). In the control group all animals showed a rejection-free posttransplantation course.
  
  
  CONCLUSIONS
  By diluting inflammatory mediators, apheresis leads to a rapid improvement in cardiac function during severe humoral rejection after head transplantation. Neither apheresis nor cyclophosphamide therapy are able to have an immediate positive influence on the activation of the immune cascade and to prevent an ongoing rejection.
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, German Heart Institute, Berlin.
authors.forename: O
authors.initials: O
authors.lastname: Grauhan
authors.forename: J
authors.initials: J
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: v Baeyer
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
authors.forename: E
authors.initials: E
authors.lastname: Fietze
authors.forename: T
authors.initials: T
authors.lastname: Cohnert
authors.forename: R
authors.initials: R
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Pfitzmann
authors.forename: H
authors.initials: H
authors.lastname: Mansfeld
authors.forename: H
authors.initials: H
authors.lastname: Siniawski
authors.forename: H
authors.initials: H
authors.lastname: Warnecke
authors.forename: R
authors.initials: R
authors.lastname: Hetzer
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis; D001781:Blood Component Removal; D003131:Combined Modality Therapy; D003348:Cortisone / Q000008:administration & dosage; D004285:Dogs; D004452:Echocardiography; D017097:Electric Impedance; D004562:Electrocardiography; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006321:Heart / Q000503:physiopathology; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000032:analysis; D007114:Immunization; D007074:Immunoglobulin G / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D009206:Myocardium / Q000473:pathology; D016042:Transplantation, Heterotopic
chemical_list: D000888:Antibodies, Anti-Idiotypic; D006649:Histocompatibility Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D003348:Cortisone