Effects of Mycophenolate Mofetil on Cardiac Allograft Survival and Cardiac Allograft Vasculopathy in Miniature Swine Margaret L. Schwarze, MD, Stuart.

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Presentation transcript:

Effects of Mycophenolate Mofetil on Cardiac Allograft Survival and Cardiac Allograft Vasculopathy in Miniature Swine Margaret L. Schwarze, MD, Stuart L. Houser, MD, Ashok Muniappan, MD, James S. Allan, MD, Matthew T. Menard, MD, Isabel McMorrow, PhD, Michaella E. Maloney, BA, Joren C. Madsen, MD, DPhil The Annals of Thoracic Surgery Volume 80, Issue 5, Pages 1787-1793 (November 2005) DOI: 10.1016/j.athoracsur.2005.04.054 Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Mycophenolic acid (MMF) and cyclosporine A (CyA) dosing. (A) The indicated dose of MMF was administered intravenously in two divided doses daily. All animals received 3 grams of MMF on the day of transplantation, and subsequent doses were adjusted based on trough serum levels and onset of diarrhea. (B) Free mycophenolic acid (MMFs primary and active metabolite) trough levels in serum were determined by high performance liquid chromatography. The target range for mycophenolic acid trough levels was 3 to 5 μg/mL (grey box), which was achieved in all animals, except number 13729, who had sub-therapeutic levels from postoperative days 4 through 7. (C) The white blood cell counts (WBC) of cardiac allograft recipients were determined daily while MMF therapy was ongoing. Two of the 3 animals, numbers 13259 and 13889, displayed a modest decline in WBC counts, which recovered after MMF therapy was completed. The remaining animal, number 13729, which also had the lowest trough MMF levels of the 3 animals, did not have any noticeable decline in WBCs. (D) Cyclosporine A trough levels were determined by fluorescence polarization immunoassay performed on whole blood. Once daily intravenous CyA dosing was given to achieve trough levels that were mainly between 400 and 800 ng/mL (grey box). (POD = postoperative day.) The Annals of Thoracic Surgery 2005 80, 1787-1793DOI: (10.1016/j.athoracsur.2005.04.054) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Histologic examination of arteries in mycophenolic acid (MMF)-treated cardiac allografts. All specimens are from necropsy. Sections are processed with an elastin stain, and vessels with an appearance consistent with cardiac allograft vasculopathy (CAV) are shown at the indicated magnification. (A) Although lesions consistent with CAV were detected in all of the MMF grafts, the prevalence of such lesions, as determined by morphometric analysis, was significantly less in MMF-treated animals than in cyclosporine A (CyA)-treated animals. (B) For comparison, a representative CAV lesion is shown with a CyA-treated animal. (POD = postoperative day.) The Annals of Thoracic Surgery 2005 80, 1787-1793DOI: (10.1016/j.athoracsur.2005.04.054) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Morphometric assessment of cardiac allograft vasculopathy (CAV) prevalence and severity in cyclosporine A (CyA)-treated and mycophenolic acid (MMF)-treated recipients of cardiac allografts. Allografts were harvested at necropsy and morphometric techniques were used to measure the incidence and grade of CAV. (A) Allografts from CyA-treated animals exhibited significantly higher prevalence of CAV compared with MMF-treated animals, (B) although the grade of CAV in both groups was similar. The Annals of Thoracic Surgery 2005 80, 1787-1793DOI: (10.1016/j.athoracsur.2005.04.054) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Cytokine expression profiles in cardiac allografts treated with mycophenolic acid (MMF). Interferon gamma (IFN-gamma), interleukin 10 (IL 10), and interleukin 15 (IL 15) cytokine transcript levels in cardiac allografts were quantified by an RNAse protection assay. Two of the three MMF-treated cardiac allografts did not have appreciable IFN-γ transcript levels. A third animal, number 13729, had significant IFN-γ expression in the allograft that was similar to the levels seen in cyclosporine A (CyA)-treated cardiac allografts. The data from the CyA-treated animal has been previously published [20]. (a.u. = arbitrary units.) The Annals of Thoracic Surgery 2005 80, 1787-1793DOI: (10.1016/j.athoracsur.2005.04.054) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Assay for production of alloantibodies in miniature swine recipients of cardiac allografts treated with either mycophenolate mofetil (MMF) or cyclosporine A (CyA). Immunoglobulin M (IgM) and immunoglobulin G (IgG) alloantibodies in the serum of MMF-treated or CyA-treated recipients were assayed by flow cytometry. No IgG or IgM alloantibody was detectable in MMF-treated recipients throughout the study period (A–C), whereas all CyA-treated animals developed IgM and IgG alloantibody before rejection, (D) (a representative animal is shown). Negative and positive control staining with sera from a naïve and donor-type sensitized animal, respectively, are shown (E). (POD = postoperative day.) The Annals of Thoracic Surgery 2005 80, 1787-1793DOI: (10.1016/j.athoracsur.2005.04.054) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions