Apoptosis in Cardiac Transplant Rejection

  • Mireia Puig
  • Navneet Narula
  • Jagat Narula

Abstract

Apoptosis is a genetically programmed process of cell death which is distinct from necrosis and occurs normally in dividing tissues. Such a process is mandatory for tissue development and growth in order to maintain the balance between new and old cells. Contrary to necrosis, apoptosis is an active energy-requiring process and is genetically programmed (Kerr 1972). Ultrastructural characterization of the process of apoptosis reveals that it involves individual cells which separates from the surrounding cells, the nucleus and cytoplasm undergo condensation, nuclear chromatin aggregates in dense masses under the nuclear envelope and intact organelles become closely packed in cytoplasmic protuberances. These protuberances are rounded by membrane and released as apoptotic bodies which are readily removed by professional scavenger or the neighboring cells. The apoptotic bodies are not accompanied by inflammatory cell infiltration because the intracellular contents are not released. The apoptotic bodies in hematoxylin-eosin stained slides are observed as small spherical or ovoid cytoplasmic bodies with pyknotic nuclear remnants (Kerr 1972). Unlike a programmed apoptotic process, necrosis involves clusters of cells; their cellular contents are exteriorized, and an intense inflammatory reaction ensues.

Keywords

Permeability Ischemia Superoxide Cysteine Electrophoresis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abbas AK. Die and let live: eliminating dangerous lymphocytes. Cell 1996;84:655–657.PubMedCrossRefGoogle Scholar
  2. 2.
    Afford SC, Hubscher S, Strain AJ, Adams DH, Neuberger JM. Apoptosis in the human liver during allograft rejection and end-stage liver disease. J Pathol 1995;176:373–380.PubMedCrossRefGoogle Scholar
  3. 3.
    Alexander DZ, Pearson TC, Hendrix R, Ritchie SC, Larsen CP. Analysis of effector mechanisms in murine cardiac allograft rejection. Transplant Immunol 1996;4:46–48.CrossRefGoogle Scholar
  4. 4.
    Ashkenazi A and Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–1308.PubMedCrossRefGoogle Scholar
  5. 5.
    Ballester M, Bordes R, Tazelaar T, Carrió I, Marrugat J, Narula J, Billingham ME. An evaluation of biopsy classification for rejection: relation to the detection of myocardial damage by 111In-monoclonal antimyosin antibody imaging. J Am Coll Cardiol 1998;31:1357–61.PubMedCrossRefGoogle Scholar
  6. 6.
    Ballester M, Carrió I. Noninvasive detection of acute cardiac rejection: the quest for the perfect test. J Nucl Cardiol 1997;4:249–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Ballester M, Obrador D, Carrió I, Moya C, Augè JM, Bordes R, Martí V, Bosch I, Bernà L, Estorch M, Pons G, Cámara ML, Padró JM, Arís A, Caralps JM. Early postoperative reduction of monoclonal antimyosin antibody uptake is associated with absent rejection-related complications after heart transplantation. Circulation 1992;85:61–68.PubMedCrossRefGoogle Scholar
  8. 8.
    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad and the ugly. Am J Physiol 1996;271(Cell Physiol 40): C1424.PubMedGoogle Scholar
  9. 9.
    Beranek JT. Apoptosis is the main mechanism of cardiomyocyte death in hyperacute rejection of heart xeno and allografts. Transplantation 1997;64:1632–1633.PubMedCrossRefGoogle Scholar
  10. 10.
    Beranek JT. Eosinophilic droplets similar to red cells are present in the hyperacute rejection of heart xenograft. J Intern Med 1997a;241:89.CrossRefGoogle Scholar
  11. 11.
    Beranek JT. Myocardial pseudovascular tubes are present in the delayed rejection of heart xenografts. Transplantation 1997b;63:3486.CrossRefGoogle Scholar
  12. 12.
    Bergese SD, Klenotic SM, Wakely ME, Sedmak DD, Orosz CG. Apoptosis in murine cardíac grafts. Transplantation 1997;63(2):320–325.PubMedCrossRefGoogle Scholar
  13. 13.
    Boonstra SG, Wever PC, Lateveer SC: Apoptosis of acinar cells in panreas allograft rejection. Translantation 1997;64:1211–1213.CrossRefGoogle Scholar
  14. 14.
    Cui S, Reichner JS, Mateo RB, Albina JE. Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or independent mechanisms. Cancer Res 1994;54:2462.Google Scholar
  15. 15.
    Dec GW, Hajjar RJ, Narula J. Apoptosis in heart failure. Cardiol Clinics 1998;16:691–710.CrossRefGoogle Scholar
  16. 16.
    Dong C, Wilson JE, Winters GL, McManus BM. Human transplant coronary artery disease. Pathological evidence of Fas-mediated apoptotic cytotoxicity in allograft arteriopathy. Lab Invest 1996;74: 921–937.PubMedGoogle Scholar
  17. 17.
    Dong C, Winters GL, Wilson JE, McManus BM. Enhanced lymphocyte longevity and absence of proliferation and lymphocyte apoptosis in Quilty effects of human heart allografts. Am J Pathol 1997;151:121–130.PubMedGoogle Scholar
  18. 18.
    Farbman AI. Electron microscope study of palate fusion in mouse embryos. Devi Biol 1968; 18:93.CrossRefGoogle Scholar
  19. 19.
    Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–389.PubMedCrossRefGoogle Scholar
  20. 20.
    Fisher GH, Rosenberg FJ, Strauss SE, Dale JK, Middelton LA, Lin AY, Strober W, Leonardo MJ, Puck JM. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935–946.PubMedCrossRefGoogle Scholar
  21. 21.
    Froelich CJ, Dixit VM, Yang X. Lymphocyte granule-mediated apoptosis: matters of viral mimicry and deadly proteases. Immunol Today 1998;19:30–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Fuks Z, Persaud RS, Alfieri A et al. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res 54:2582–2890.Google Scholar
  23. 23.
    Fyfe A, Daly P, Galligan L, Pirc L, Feindel C, Cardella C. Coronary sinus sampling of cytokines after heart transplantation: evidence for macrophage activation and interleukin-4 production within the graft. J Am Coll Cardiol 1993;21:171.PubMedCrossRefGoogle Scholar
  24. 24.
    Gapany C, Zhao M, Zimmermann A. The apoptosis protector, bcl-2 protein, is downregulated in bile duct epithelial cells of human liver allografts. J Hepatol 1997;26:535–542.PubMedCrossRefGoogle Scholar
  25. 25.
    Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 1994;330: 1431–1438.PubMedCrossRefGoogle Scholar
  26. 26.
    Glüksmann A. Cell death in normal vertebrate ontogeny. Biol Rev 1951;26:59.CrossRefGoogle Scholar
  27. 27.
    Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ. Cytotoxic lymphocytes require granz-ime B for the rapid induction of DNA fragmentation and apoptosis in allogenic target cells. Cell 1994;76:977–987.PubMedCrossRefGoogle Scholar
  28. 28.
    Hori S, Havaux X, Rubay R, Latinne D, Bazin H, Gianello P. Effects of graft preservation and IgM depletion on guinea pig to rat cardiac xenograft survival. Transplantation 1997;63:1554.PubMedCrossRefGoogle Scholar
  29. 29.
    Hosenpud JD. Noninvasive diagnosis of cardiac allograft rejection. Another of many searches for the grail. Circulation 1992;85:368–371.PubMedCrossRefGoogle Scholar
  30. 30.
    Hruban RH, Beschorner WE, Baumgartner WA, Augustine SM, Ren H, Reitz BA, Hutchins GM. Accelerated arteriosclerosis in heart transplant recipients is associated with a T-lymphocyte-mediated endothelialitis. Am J Pathol 1990;137:871–881.PubMedGoogle Scholar
  31. 31.
    Ito H, Kasagi N, Shomori K, Osaki M, Adachi H. Apoptosis in the human allografted kidney. Analysis by terminal deoxynucleotidyl transferase-mediated dUTP-botin nick end labeling. Transplantation 1995;60(8):794–798.PubMedGoogle Scholar
  32. 32.
    James TN. Complete heart block and fatal right ventricular failure in an infant. Circulation 1996; 1588–1600.Google Scholar
  33. 33.
    Jollow KC, Sundstorm JB, Gravanis MB, Ka-ter K, Herskowitz A, Ansari AA. Apoptosis of mononuclear cell infiltrates in cardiac allograft biopsy specimens questions studies of biopsy cultured cells. Transplantation 1997;63:1487–1489.CrossRefGoogle Scholar
  34. 34.
    Kageyama Y, Li XK, Suzuki S, Suzuki H, Suzuki K, Kazui T, Harada Y. Apoptosis is involved in acute cardiac allograft rejection in rats. Ann Thorac Surg 1998;65:1604–1609.PubMedCrossRefGoogle Scholar
  35. 35.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.PubMedCrossRefGoogle Scholar
  36. 36.
    Kerr JFR. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J Path Bact 1965;90:419.PubMedCrossRefGoogle Scholar
  37. 37.
    Kerr JFR. Shrinkage necrosis: a distinct mode of cellular death. J Pathol 1971; 105:13.PubMedCrossRefGoogle Scholar
  38. 38.
    Knoop M, McMahon RFT, Jones CJP, Hutchinson IV Apoptosis in pancreatic allograft rejection-ultrastuctural observations. Exp Pathol 1991;41:219–224.PubMedCrossRefGoogle Scholar
  39. 39.
    Kondo S, Yin D, Aoki T, Takahashi J, Morimura T, Takeuchi J. Bcl-2 gene prevents apoptosis of basic fibroblast growth factor-deprived murine aortic endothelial cells. Exp Cell Res 1994;213: 428–432.PubMedCrossRefGoogle Scholar
  40. 40.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627.PubMedCrossRefGoogle Scholar
  41. 41.
    Laguens RP, Cabeza Meckert PM, San Martino J, Perrone S, Favaloro S. Identification of programmed cell death (apoptosis) in situ by means of specific labeling of nuclear DNA fragments in heart biopsy samples during acute rejection episodes. J Heart Lung Transplant 1996;15:911–918.PubMedGoogle Scholar
  42. 42.
    Laine J, Etelämäki P, Holmberg C, Dunkel L. Apoptotic cell death in human chronic renal allograft rejection. Transplantation 1997;63(1): 101–105.PubMedCrossRefGoogle Scholar
  43. 43.
    Larsen C, Elwwod D, Alexander D et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996;381:434.PubMedCrossRefGoogle Scholar
  44. 44.
    Larsen CP, Alexander DZ, Hendrix R, Ritchie SC, Pearson TC. Fas-mediated cytotoxicity: an immunoeffector or immunoregulators pathway in T cell mediated immune responses. Transplantation 1995;60:221–224.PubMedCrossRefGoogle Scholar
  45. 45.
    Lee RG, Nakamura K, Tsamandas AC et al. Pathology of human intestinal transplantation. Gastrenterology 1996a; 110:1820–1834.CrossRefGoogle Scholar
  46. 46.
    Lee RG, Tsamanda AC, Abu-Elmagd K et al. Histologic spectrum of acute cellular rejection in human intestinal allografts. Transplant Proc 1996b;28(5):2767.Google Scholar
  47. 47.
    Li P, Nijhawan D, Budihardjo I, Srinivasulo SM, Ahmed M, Alnemri ES, Wang X. Cytochrome C and dATP dependent formation of Apaf-1/Caspase 9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts requirements for dATP and Cytochrome C. Cell 1996;86:147–157.PubMedCrossRefGoogle Scholar
  49. 49.
    Luo X, Budihardjol I, Zon H, Slaughter C, Wang X. Bid, a Bcl-2 interacting protein, mediates Cytochrome C release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481–490.PubMedCrossRefGoogle Scholar
  50. 50.
    Mallat Z, Tedgui A, Fontaliran F et al. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996;335:1190–1197.PubMedCrossRefGoogle Scholar
  51. 51.
    Marsh CB, Anderson CL. Lowe MP, Wewers MD. Monocyte IL-8 release is induced by two independent Fc gamma-R-mediated pathways. J Immunol 1996;157:2632–2637.PubMedGoogle Scholar
  52. 52.
    Marsh CB, Gadek JE, Kindt GC, Moore SA, Wewers MD. Monocyte Fc gamma receptor cross-linking induces IL-8 production. J Immunol 1995;155:3161.PubMedGoogle Scholar
  53. 53.
    Marsh CB, Love MP, Rovin BH, Parker JM, Liao Z, Knoell DL, Wewers MD. Lymphocytes produce IL-1 beta in response to Fc gamma receptor cross-linking effects on parenchymal cell IL-8 release. J Immunol 1998;160:3942–3948.PubMedGoogle Scholar
  54. 54.
    Marsh CB, Wewers MD, Tan LC, Robin BH. Fc gamma receptor cross-linking induces peripheral blood mononuclear cell MCP-1 expression. J Immunol 1997a;158:1078–1084.Google Scholar
  55. 55.
    Matsuno T, Nakagawa K, Sasaki H et al. Apoptosis in acute tubular necrosis and acute renal allograft rejection. Transplant Proc 1994;26(4):2170–2173.PubMedGoogle Scholar
  56. 56.
    Matsuno T, Sasaki H, Nakagawa K et al. Fas antigen expression and apoptosis in kidney allografts. Trasplant Proc 1997;29:177–178.CrossRefGoogle Scholar
  57. 57.
    McConkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. J Leukoc Biol 1996;59:775.PubMedGoogle Scholar
  58. 58.
    Miyakawi T, Uehara T, Nibu R, Tsuji I, Yachie A, Yonehara S, Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 1992;149:3753–3758.Google Scholar
  59. 59.
    Nagata S, Suda T. Fas and Fas-Ligand: lpr and gld mutations. Immunol Today 1995;16:39–43.PubMedCrossRefGoogle Scholar
  60. 60.
    Nagata S. Apoptosis by death factor. Cell 1997;88:355–365.PubMedCrossRefGoogle Scholar
  61. 61.
    Narula J, Chandrashekhar Y, Dec GW. Apoptosis in heart failure: a saga of heightened expectations, unfulfilled promises and broken hearts… Apoptosis, 1999;3:309–315.CrossRefGoogle Scholar
  62. 62.
    Narula J, Haider N, Virmani R et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182–1189.PubMedCrossRefGoogle Scholar
  63. 63.
    Narula J, Kharbanda S, Khaw BA. Apoptosis in heart disease. Chest 1997;112:1358–1362.PubMedCrossRefGoogle Scholar
  64. 64.
    Kharbanda S, Pandey P, Saxena S, Haider N, Iskandrian AE, Narula J. Translocation of SAPK to mitochondria and release of cytochrome C during apoptosis. Circulation 1998;98:683.Google Scholar
  65. 65.
    Nathan C. Natural resistance and nitric oxide. Cell 1995;82:873.PubMedCrossRefGoogle Scholar
  66. 66.
    Nawaz S, Fennell RH. Apoptosis of bile duct epithelial cells in hepatic allograft rejection. Histopathology 1994;25:137–142.PubMedCrossRefGoogle Scholar
  67. 67.
    Olsen S, Burdick JF, Keown PA, Wallace AC, Racusen LC, Solez K. Primary acute renal failure (“Acute tubular necrosis”) in the transplanted kidney: Morphology and pathogenesis. Medicine 1989; 68(3):173–187.PubMedCrossRefGoogle Scholar
  68. 68.
    Pinsky DJ, Cai B, Yang X, Rodriguez C, Sciacca RR, Marsh CB. The letal effects of cytokine induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. J Clin Invest 1995;95:677–685.PubMedCrossRefGoogle Scholar
  69. 69.
    Puig M, Ballester M, Matias-Guiu X, Bordes R, Carrió I, Aymat MR, Marrugat J, Padró JM, Caralps JM, Narula J. Apoptosis of myocytes in cardiac allograft rejection: An additional mechanism of myocardial damage away from Foci of Myocyte Necrosis (submitted for publication, 1998).Google Scholar
  70. 70.
    Reiter Y, Ciobotariu A, Jones J, Morgan BP, Fishelson Z. Complement membrane attack complex, perforin, and bacterial exotoxins induce in K562 cells calcium-dependent cross-protection from lysis. J Immunol 1995;155:2203.Google Scholar
  71. 71.
    Rieux-Laucaut F, Le Deist F, Hivroz C, Rogerts IAG, Debatin KM, Fischer A, Villartay JP. Mutations in Fas associated with human lymphoproliferative syndrome and auto immunity. Science 1995;268:1347–1349.CrossRefGoogle Scholar
  72. 72.
    Rose AG, Cooper DK. A histopathologic grading system of hyperacute (humoral, antibody-mediated) cardiac xenograft and allograft rejection. J Heart Lung Transplant 1996:15:804.PubMedGoogle Scholar
  73. 73.
    Sashida H, Uchida K, Abiko Y. Changes in cardiac ultrastructure and myofibrillar proteins during ischemia in dogs, with special reference to changes in Z lines. J Moll Cell Cardiol 1984; 16:1161.CrossRefGoogle Scholar
  74. 74.
    Saunders JW. Death in embryonic systems. Science 1966; 154:604.PubMedCrossRefGoogle Scholar
  75. 75.
    Singer GG, Abbas AK. The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1994;1:365–371.PubMedCrossRefGoogle Scholar
  76. 76.
    Steel GG. Cell loss as a factor in the growth rate of human tumors. Eur J Cancer 1967;3:381.PubMedGoogle Scholar
  77. 77.
    Szabolcs M, Michler RE, Yang X et al. Apoptosis of cardiac myocytes during cardiac allograft rejection. Relation to induction of nitric oxide synthase. Circulation 1996;94(7): 1665–1673.PubMedCrossRefGoogle Scholar
  78. 78.
    Szabolcs MJ, Rawalli S, Minanov O, Sciacca R, Michler RE, cannon PJ. Apoptosis and increased expression of inducible nitric oxide synthetase in human allograft rejection. Transplantation 1998;65:804–812.PubMedCrossRefGoogle Scholar
  79. 79.
    Torre-Amione G, MacLellan W, Kapadia S, Weilbacher D, Farmer J, Young J, Mann D. Tumor necrosis factor-alpha is persistently expressed in cardiac allografts in the absence of histological or clinical evidence of rejection. Transplant Proc 1998;30:875–877.PubMedCrossRefGoogle Scholar
  80. 80.
    Tschopp J, Nabholz M. Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol 1990;8:279–302.PubMedCrossRefGoogle Scholar
  81. 81.
    Wewers MD, Marsh CB. Role of the antibody in the pathogenesis of transplant vascular sclerosis: a hypothesis. Transplant Immunol 1997;5:283–288.CrossRefGoogle Scholar
  82. 82.
    White WL, Zhang YL, Shelby J et al. Myocardial apoptosis in a heterotopic murine heart transplantation model of chronic rejection and graft vasculopathy. J Heart Lung Transplant 1997;16:250–255.PubMedGoogle Scholar
  83. 83.
    Wu C, Lovett M, Wong-hee J et al. Cytokine gene expression in rejecting cardiac allografts. Transplantation 1992;54:236.CrossRefGoogle Scholar
  84. 84.
    Yeh ETH. Life and death of cell. Hospital Practice. August 15, 1998;85–92.Google Scholar
  85. 85.
    Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 1993;92:2303–2312.PubMedCrossRefGoogle Scholar
  86. 86.
    Yoshida K, Inui M, Harda K et al. Reperfusion of rat heart after brief ischemia induces proteolysis of calspectin (non-erythroid spectrin) during apoptosis. J Biol Chem 1995;270:6425.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Mireia Puig
    • 1
  • Navneet Narula
    • 2
  • Jagat Narula
    • 1
  1. 1.Center for Heart Failure, Transplantation ResearchHahnemann University HospitalPhiladelphiaUSA
  2. 2.Department of RadiologyHahnemann University HospitalPhiladelphiaUSA

Personalised recommendations