Thorac Cardiovasc Surg 2009; 57(4): 191-195
DOI: 10.1055/s-0029-1185395
Original Cardiovascular

© Georg Thieme Verlag KG Stuttgart · New York

Alpha-Gal Specific IgG Immune Response after Implantation of Bioprostheses

A. Mangold1 , T. Szerafin2 , K. Hoetzenecker1 , S. Hacker1 , M. Lichtenauer1 , T. Niederpold1 , S. Nickl1 , M. Dworschak3 , R. Blumer4 , J. Auer5 , H. J. Ankersmit1
  • 1Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria
  • 2Institute of Cardiology, University of Debrecen, Debrecen, Hungary
  • 3Department of Anesthetics, Medical University of Vienna, Vienna, Austria
  • 4Department of Anatomy, Medical University of Vienna, Vienna, Austria
  • 5Department of Internal Medicine I, Hospital St. Josef Braunau, Braunau, Austria
Further Information

Publication History

received October 2, 2008

Publication Date:
20 May 2009 (online)


Background: We have previously shown that the α‐Gal (Galα1.3-Galβ1–4GlcNAc-R) epitope is a relevant xenoantigen present on bioprostheses utilized in cardiac surgery and elicits an α‐Gal specific IgM immune response. We sought to investigate whether that immune response continues after valve implantation. Materials and Methods: We collected plasma samples from patients who underwent bioprosthesis implantation (n = 19) or mechanical valve replacement (n = 8), respectively, prior to, at 10 days and at 3 months after cardiac surgery. ELISA was utilized to quantify α‐Gal specific IgG and IgG subclasses. 3 bioprosthetic tissue samples were obtained from patients who had to undergo re-operation within 1 week (n = 1) or at 12–15 months (n = 2) after the initial operation. We utilized confocal laser scanning microscopy (CLSM) to detect the presence of α‐Gal epitopes (IB4) and cell nuclei (DAPI). Results: α‐Gal specific IgG was significantly increased 3 months after implantation of bioprostheses compared to preoperative values (p < 0.001) and was significantly higher than α‐Gal specific IgG levels of the control group (p < 0.05). IgG3 was the major subclass directed against α‐Gal (p < 0.05, pre- vs. postoperative values). In CLSM analysis we demonstrated that bioprostheses explanted 1 week after implantation contained IB4/DAPI positive cells within the collagen matrix. In contrast, in patients who underwent reoperation after 12 months, porcine tissue showed a complete lack of IB4/DAPI. Conclusion: Our results indicate that the implantation of bioprostheses elicits a specific humoral immune response against α‐Gal bearing cells compared to controls within 3 months after cardiac surgery. The complete absence of IB4/DAPI positive structures 12 months after implantation indicates a specific degradation of α‐Gal bearing cells through previous exposure to the human blood circuit.


  • 1 Galili U, Clark M R, Shohet S B, Buehler J, Macher B A. Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1–3Gal epitope in primates.  Proc Natl Acad Sci USA. 1987;  84 1369-1373
  • 2 Galili U, Macher B A, Buehler J, Shohet S B. Human natural anti-alpha-galactosyl IgG. II. The specific recognition of alpha (1–3)-linked galactose residues.  J Exp Med. 1985;  162 573-582
  • 3 Galili U, Rachmilewitz E A, Peleg A, Flechner I. A unique natural human IgG antibody with anti-alpha-galactosyl specificity.  J Exp Med. 1984;  160 1519-1531
  • 4 Sandrin M S, Vaughan H A, Dabkowski P L, McKenzie I F. Anti-pig IgM antibodies in human serum react predominantly with Gal(alpha 1–3)Gal epitopes.  Proc Natl Acad Sci USA. 1993;  90 11391-11395
  • 5 Galili U. Xenotransplantation and ABO incompatible transplantation: the similarities they share.  Transfus Apher Sci. 2006;  35 45-58
  • 6 Galili U, Mandrell R E, Hamadeh R M, Shohet S B, Griffiss J M. Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora.  Infect Immun. 1988;  56 1730-1737
  • 7 Gallili U. The alpha-gal epitope (Gal alpha 1–3Gal beta 1–4GlcNAc-R) in xenotransplantation.  Biochimie. 2001;  83 557-563
  • 8 Bonow R O, Carabello B A, Kanu C, de Leon Jr A C, Faxon D P, Freed M D. et al . ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.  Circulation. 2006;  114 e84-e231
  • 9 Hammermeister K, Sethi G K, Henderson W G, Grover F L, Oprian C, Rahimtoola S H. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial.  J Am Coll Cardiol. 2000;  36 1152-1158
  • 10 Akins C W, Hilgenberg A D, Vlahakes G J, MacGillivray T E, Torchiana D F, Madsen J C. Results of bioprosthetic versus mechanical aortic valve replacement performed with concomitant coronary artery bypass grafting.  Ann Thorac Surg. 2002;  74 1098-1106
  • 11 Schoen F J, Levy R J. Calcification of tissue heart valve substitutes: progress toward understanding and prevention.  Ann Thorac Surg. 2005;  79 1072-1080
  • 12 Human P, Zilla P. Inflammatory and immune processes: the neglected villain of bioprosthetic degeneration?.  J Long Term Eff Med Implants. 2001;  11 199-220
  • 13 Zilla P, Brink J, Human P, Bezuidenhout D. Prosthetic heart valves: catering for the few.  Biomaterials. 2008;  29 385-406
  • 14 Laitinen L. Griffonia simplicifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues.  Histochem J. 1987;  19 225-234
  • 15 Konakci K Z, Bohle B, Blumer R, Hoetzenecker W, Roth G, Moser B. et al . Alpha-Gal on bioprostheses: xenograft immune response in cardiac surgery.  Eur J Clin Invest. 2005;  35 17-23
  • 16 Stavnezer J. Immunoglobulin class switching.  Curr Opin Immunol. 1996;  8 199-205
  • 17 Ishizaka T, Ishizaka K, Salmon S, Fudenberg H. Biologic activities of aggregated gamma-globulin. 8. Aggregated immunoglobulins of different classes.  J Immunol. 1967;  99 82-91
  • 18 Schumaker V N, Calcott M A, Spiegelberg H L, Muller-Eberhard H J. Ultracentifuge studies of the binding of IgG of different subclasses to the Clq subunit of the first component of complement.  Biochemistry. 1976;  15 5175-5181
  • 19 Michaelsen T E, Garred P, Aase A. Human IgG subclass pattern of inducing complement-mediated cytolysis depends on antigen concentration and to a lesser extent on epitope patchiness, antibody affinity and complement concentration.  Eur J Immunol. 1991;  21 11-16
  • 20 Bredius R G, Fijen C A, De Haas M, Kuijper E J, Weening R S, Van de Winkel J G. et al . Role of neutrophil Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16) polymorphic forms in phagocytosis of human IgG1- and IgG3-opsonized bacteria and erythrocytes.  Immunology. 1994;  83 624-630
  • 21 Huizinga T W, Kerst M, Nuyens J H, Vlug A, von dem Borne A E, Roos D. et al . Binding characteristics of dimeric IgG subclass complexes to human neutrophils.  J Immunol. 1989;  142 2359-2364
  • 22 Parren P W, Warmerdam P A, Boeije L C, Arts J, Westerdaal N A, Vlug A. et al . On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2.  J Clin Invest. 1992;  90 1537-1546
  • 23 Salgaller M L, Bajpai P K. Immunogenicity of glutaraldehyde-treated bovine pericardial tissue xenografts in rabbits.  J Biomed Mater Res. 1985;  19 1-12
  • 24 Rocchini A P, Weesner K M, Heidelberger K, Keren D, Behrendt D, Rosenthal A. Porcine xenograft valve failure in children: an immunologic response.  Circulation. 1981;  64 II162-II171
  • 25 Manji R A, Zhu L F, Nijjar N K, Rayner D C, Korbutt G S, Churchill T A. et al . Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection.  Circulation. 2006;  114 318-327
  • 26 Chen R H, Kadner A, Mitchell R N, Adams D H. Fresh porcine cardiac valves are not rejected in primates.  Thorac Cardiov Surg. 2000;  119 1216-1220
  • 27 Farivar R S, Filsoufi F, Adams D H. Mechanisms of Gal(alpha)1–3Gal(beta)1–4GlcNAc-R (alphaGal) expression on porcine valve endothelial cells.  Thorac Cardiovasc Surg. 2003;  125 306-314
  • 28 Kasimir M T, Rieder E, Seebacher G, Wolner E, Weigel G, Simon P. Presence and elimination of the xenoantigen gal (alpha1, 3) gal in tissue-engineered heart valves.  Tissue Eng. 2005;  11 1274-1280
  • 29 Bonow R O, Carabello B A, Chatterjee K, de Leon Jr A C, Faxon D P, Freed M D. et al . Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.  Circulation. 2008;  118 e523-e661
  • 30 Ye J, Cheung A, Lichtenstein S V, Pasupati S, Carere R G, Thompson C R. et al . Six-month outcome of transapical transcatheter aortic valve implantation in the initial seven patients.  Eur J Cardiothorac Surg. 2007;  31 16-21
  • 31 Walther T, Falk V, Kempfert J, Borger M A, Fassl J, Chu M W. et al . Transapical minimally invasive aortic valve implantation; the initial 50 patients.  Eur J Cardiothorac Surg. 2008;  33 983-988

Doz. Dr. Hendrik Jan Ankersmit

Medical University of Vienna
Department of Cardiothoracic Surgery

Währinger Gürtel 18–20

1090 Vienna


Phone: + 43 14 04 00 68 57