(Circulation. 1999;100:67-74.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Rapamycin Reverses Chronic Graft Vascular Disease in a Novel Cardiac Allograft Model
Presented at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-648–I-649).
From Stanford University School of Medicine, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford, Calif.
Correspondence to Robert C. Robbins, MD, Assistant Professor of Cardiothoracic Surgery, Stanford University Medical Center, Falk Cardiovascular Research Center, Stanford, CA 94305. E-mail robbins{at}leland.stanford.edu
Background—Chronic graft vascular disease (CGVD) in cardiac allografts has been defined as a slowly evolving vasculopathy unresponsive to conventional immunosuppression. We compared 4 rodent models of CGVD to evaluate the reproducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine (CSA) were then used to treat CGVD.
Methods and Results—Hearts were harvested and placed heterotopically into allogenic recipients. CGVD scores of PVG allografts from ACI recipients treated with CSA on days 1 through 10 were significantly elevated on day 90 (n=16) compared with other models (immunosuppression used): (1) Lewis to F344 recipients (CSA), (2) Brown Norway to Lewis (FK506), and (3) DA to Wistar-Firth (methylprednisolone, azathioprine, CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n=6), delayed Rapa (3 mg · kg-1 · d-1 IP) reversed CGVD in PVG grafts (0.22±0.19 on day 90, n=6). ACI isografts showed no evidence of CGVD (n=6) at day 90. Immunohistochemistry of PVG grafts revealed perivascular infiltrates consisting of CD4+ T cells and limited numbers of macrophages persisting up to day 90. Flow cytometry demonstrated increased levels of anti-donor antibody at day 90, which was significantly inhibited by Rapa treatment.
Conclusions—PVG grafts developed a significant increase in CGVD without evidence of ongoing myocardial rejection. This CGVD appeared to be mediated by both cellular and humoral mechanisms, given CD4+ perivascular infiltrates and increased levels of anti-donor antibody. The anti-CGVD effectiveness of Rapa during a period in which there was little myocardial cellular infiltrate supports a novel mechanism of effect such as smooth muscle or B-cell inhibition.
Key Words: transplantation • immunology • coronary disease • antibodies • immunohistochemistry
This article has been cited by other articles:
 |
|
 |
|
  B. P. Griffith, M. Haddad, and R. S. Poston Immunobiology of Heart and Heart-Lung Transplantation Card. Surg. Adult, January 1, 2008; 3(2008): 1513 - 1538. [Full Text]
|
|
|
|
 |
|
 E. Raichlin, J.-H. Bae, Z. Khalpey, B. S. Edwards, W. K. Kremers, A. L. Clavell, R. J. Rodeheffer, R. P. Frantz, C. Rihal, A. Lerman, et al. Conversion to Sirolimus as Primary Immunosuppression Attenuates the Progression of Allograft Vasculopathy After Cardiac Transplantation Circulation, December 4, 2007; 116(23): 2726 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ramzy, V. Rao, L. C. Tumiati, N. Xu, S. Miriuka, D. Delgado, and H. J. Ross Role Of Endothelin-1 and Nitric Oxide Bioavailability in Transplant-Related Vascular Injury: Comparative Effects of Rapamycin and Cyclosporine Circulation, July 4, 2006; 114(1_suppl): I-214 - I-219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Isobe, H. Kosuge, and J.-i. Suzuki T Cell Costimulation in the Development of Cardiac Allograft Vasculopathy: Potential Targets for Therapeutic Interventions Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1447 - 1456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Stallone, B. Infante, A. Schena, M. Battaglia, P. Ditonno, A. Loverre, L. Gesualdo, F. P. Schena, and G. Grandaliano Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3755 - 3762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lindenfeld, G. G. Miller, S. F. Shakar, R. Zolty, B. D. Lowes, E. E. Wolfel, L. Mestroni, R. L. Page II, and J. Kobashigawa Drug Therapy in the Heart Transplant Recipient: Part II: Immunosuppressive Drugs Circulation, December 21, 2004; 110(25): 3858 - 3865. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Waksman, A. E. Ajani, A. D. Pichard, R. Torguson, E. Pinnow, D. Canos, L. F. Satler, K. M. Kent, P. Kuchulakanti, C. Pappas, et al. Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions: The Oral Rapamune to Inhibit Restenosis (ORBIT) study J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1386 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Andres Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential Cardiovasc Res, July 1, 2004; 63(1): 11 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Schachner, Y. Zou, A. Oberhuber, A. Tzankov, T. Mairinger, G. Laufer, and J. O. Bonatti Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts Ann. Thorac. Surg., May 1, 2004; 77(5): 1580 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zohlnhofer, T. G. Nuhrenberg, F.-J. Neumann, T. Richter, A. E. May, R. Schmidt, K. Denker, M. A. Clauss, A. Schomig, and P. A. Baeuerle Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties Mol. Pharmacol., April 1, 2004; 65(4): 880 - 889. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. S. Poston and B. P. Griffith Heart Transplantation J Intensive Care Med, January 1, 2004; 19(1): 3 - 12. [Abstract] [PDF]
|
|
|
|
|
|
X. M. Mueller Drug immunosuppression therapy for adult heart transplantation. Part 2: clinical applications and results Ann. Thorac. Surg., January 1, 2004; 77(1): 363 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Murphy and M. L. Nicholson Rapamycin has no effect on fibrosis-associated gene expression or extracellular matrix accumulation when administered to animals with established or early allograft vasculopathy J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 2058 - 2064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Edelman and H. D. Danenberg Rapamycin for Cardiac Transplant Rejection and Vasculopathy: One Stone, Two Birds? Circulation, July 8, 2003; 108(1): 6 - 8. [Full Text] [PDF]
|
|
|
|
|
|
D. Mancini, S. Pinney, D. Burkhoff, J. LaManca, S. Itescu, E. Burke, N. Edwards, M. Oz, and A. R. Marks Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy Circulation, July 8, 2003; 108(1): 48 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Vassalli, A. Gallino, M. Weis, W. von Scheidt, L. Kappenberger, L.K. von Segesser, J.-J. Goy, and on behalf of the Working Group Microcirculation of Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy Eur. Heart J., July 1, 2003; 24(13): 1180 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Dambrin, J. Klupp, T. Birsan, J. Luna, T. Suzuki, T. Lam, P. Stahr, B. Hausen, U. Christians, P. Fitzgerald, et al. Sirolimus (Rapamycin) Monotherapy Prevents Graft Vascular Disease in Nonhuman Primate Recipients of Orthotopic Aortic Allografts Circulation, May 13, 2003; 107(18): 2369 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Griffith and R. S. Poston Immunobiology of Heart and Heart-Lung Transplantation Card. Surg. Adult, January 1, 2003; 2(2003): 1403 - 1426. [Full Text]
|
|
|
|
|
|
B. Cantin, P. Wen, D. Zhu, M. Dai, S. N. Panchal, M. E. Billingham, J. K. Gwathmey, and H. A. Valantine Transplant Coronary Artery Disease: A Novel Model Independent of Cellular Alloimmune Response Circulation, November 20, 2001; 104(21): 2615 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Regar, G Sianos, and P W Serruys Stent development and local drug delivery Br. Med. Bull., October 1, 2001; 59(1): 227 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O. Marx and A. R. Marks Bench to Bedside: The Development of Rapamycin and Its Application to Stent Restenosis Circulation, August 21, 2001; 104(8): 852 - 855. [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Mahoney, A. S. Weyrich, D. A. Dixon, T. McIntyre, S. M. Prescott, and G. A. Zimmerman Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes PNAS, August 17, 2001; (2001) 181201398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sun, S. O. Marx, H.-J. Chen, M. Poon, A. R. Marks, and L. E. Rabbani Role for p27Kip1 in Vascular Smooth Muscle Cell Migration Circulation, June 19, 2001; 103(24): 2967 - 2972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sata, Z. Luo, and K. Walsh Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia J. Immunol., June 1, 2001; 166(11): 6964 - 6971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. NISHIMURA, J. L. FAUL, G. J. BERRY, I. VEVE, R. G. PEARL, and P. N. KAO 40-O-(2-Hydroxyethyl)-rapamycin Attenuates Pulmonary Arterial Hypertension and Neointimal Formation in Rats Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 498 - 502. [Abstract] [Full Text]
|
|
|
|
|
|
J. E. Sousa, M. A. Costa, A. Abizaid, A. S. Abizaid, F. Feres, I. M. F. Pinto, A. C. Seixas, R. Staico, L. A. Mattos, A. G. M. R. Sousa, et al. Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries : A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study Circulation, January 16, 2001; 103(2): 192 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Mahoney, A. S. Weyrich, D. A. Dixon, T. McIntyre, S. M. Prescott, and G. A. Zimmerman Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes PNAS, August 28, 2001; 98(18): 10284 - 10289. [Abstract] [Full Text] [PDF]
|
|