Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation


Although over 50 years have passed since its first laboratory description, intentional induction of immune tolerance to foreign antigens has remained an elusive clinical goal. We previously reported that the requirement for ABO compatibility in heart transplantation is not applicable to infants. Here, we show that ABO-incompatible heart transplantation during infancy results in development of B-cell tolerance to donor blood group A and B antigens. This mimics animal models of neonatal tolerance and indicates that the human infant is susceptible to intentional tolerance induction. Tolerance in this setting occurs by elimination of donor-reactive B lymphocytes and may be dependent upon persistence of some degree of antigen expression. These findings suggest that intentional exposure to nonself A and B antigens may prolong the window of opportunity for ABO-incompatible transplantation, and have profound implications for clinical research on tolerance induction to T-independent antigens relevant to xenotransplantation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Development of serum A-specific and B-specific antibodies in recipients of ABO-incompatible and ABO-compatible heart transplants showing a persistent and selective deficiency in donor-specific antibody.
Figure 2: Immunohistochemical staining showing absence of complement deposition and persistence of donor antigens within endomyocardial biopsy specimens from ABO-incompatible graft recipients.
Figure 3: ELISA analyses of antibody in PBMC culture supernatants showing absence of A-specific antibody production by PBMC from two A→O recipients.
Figure 4: Visualization of antibody-producing cells by ELISPOT assay showing absence of A-specific and B-specific antibody-producing cells in cultured PBMC isolated from A→O (a,b), B→O (c,d) and O→O (e,f) heart transplant recipients.
Figure 5: Detection by flow cytometry of B lymphocytes bearing BCR specific to A antigen in PBMC isolated from infant heart transplant recipients.


  1. 1

    Alexandre, G.P. et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant. Proc. 19, 4538–4542 (1987).

    CAS  Google Scholar 

  2. 2

    Sutherland, D.E. et al. Long-term effect of splenectomy versus no splenectomy in renal transplant patients. Reanalysis of a randomized prospective study. Transplantation 38, 619–624 (1984).

    CAS  Article  Google Scholar 

  3. 3

    Bannett, A.D., McAlack, R.F., Morris, M., Chopek, M.W. & Platt, J.L. ABO incompatible renal transplantation: a qualitative analysis of native endothelial tissue ABO antigens after transplantation. Transplant. Proc. 21, 783–785 (1989).

    CAS  Google Scholar 

  4. 4

    Chopek, M.W., Simmons, R.L. & Platt, J.L. ABO-incompatible kidney transplantation: initial immunopathologic evaluation. Transplant. Proc. 19, 4553–4557 (1987).

    CAS  Google Scholar 

  5. 5

    Cooper, D.K. A clinical survey of cardiac transplantation between ABO blood group-incompatible recipients and donors. Transplant Proc. 22, 1457 (1990).

    CAS  Google Scholar 

  6. 6

    Gugenheim, J., Samuel, D., Reynes, M. & Bismuth, H. Liver transplantation across ABO blood group barriers. Lancet 336, 519–523 (1990).

    CAS  Article  Google Scholar 

  7. 7

    Owen, R.D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–405 (1945).

    CAS  Article  Google Scholar 

  8. 8

    Burnet, F.M. & Fenner, F. The Production of Antibodies. (Macmillan and Company, Melbourne, 1949).

    Google Scholar 

  9. 9

    Billingham, R.E., Brent, L. & Medawar, P.B. Activity acquired tolerance of foreign cells. Nature 172, 603–606 (1953).

    CAS  Article  Google Scholar 

  10. 10

    Dorsch, S. & Roser, B. Suppressor cells in transplantation tolerance. I. Analysis of the suppressor status of neonatally and adoptively tolerized rats. Transplantation 33, 518–524 (1982).

    CAS  Article  Google Scholar 

  11. 11

    Kappler, J.W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987).

    CAS  Article  Google Scholar 

  12. 12

    Klinman, N.R. The “clonal selection hypothesis” and current concepts of B cell tolerance. Immunity 5, 189–195 (1996).

    CAS  Article  Google Scholar 

  13. 13

    McCarthy, S.A. & Bach, F.H. The cellular mechanism of maintenance of neonatally induced tolerance to H-2 class I antigens. J. Immunol. 131, 1676–1682 (1983).

    CAS  Google Scholar 

  14. 14

    Ramsdell, F. & Fowlkes, B.J. Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science 248, 1342–1348 (1990).

    CAS  Article  Google Scholar 

  15. 15

    Ramsdell, F., Lantz, T. & Fowlkes, B.J. A nondeletional mechanism of thymic self tolerance. Science 246, 1038–1041 (1989).

    CAS  Article  Google Scholar 

  16. 16

    Streilein, J.W. Neonatal tolerance of H-2 alloantigens. Procuring graft acceptance the “old-fashioned” way. Transplantation 52, 1–10 (1991).

    CAS  Article  Google Scholar 

  17. 17

    West, L.J. Defining critical windows in the development of the human immune system. Hum. Exp. Toxicol. 21, 499–505 (2002).

    CAS  Article  Google Scholar 

  18. 18

    West, L.J. Developmental aspects of immunomodulation: exploiting the immature immune system for organ transplantation. Transpl. Immunol. 9, 149–153 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Cadoz, M. Potential and limitations of polysaccharide vaccines in infancy. Vaccine 16, 1391–1395 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Gennery, A.R. et al. Effect of immunosuppression after cardiac transplantation in early childhood on antibody response to polysaccharide antigen. Lancet 351, 1778–1781 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Wilson, C.B. Immunologic basis for increased susceptibility of the neonate to infection. J. Pediatr. 108, 1–12 (1986).

    CAS  Article  Google Scholar 

  22. 22

    Fong, S.W., Qaqundah, B.Y. & Taylor, W.F. Developmental patterns of ABO isoagglutinins in normal children correlated with the effects of age, sex., and maternal isoagglutinins. Transfusion 14, 551–559 (1974).

    CAS  Article  Google Scholar 

  23. 23

    Springer, G.F. & Horton, R.E. Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J. Clin. Invest. 48, 1280–1291 (1969).

    CAS  Article  Google Scholar 

  24. 24

    West, L.J. et al. ABO-incompatible heart transplantation in infants. N. Engl. J. Med. 344, 793–800 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Smalley, C.E. & Tucker, E.M. Blood group A antigen site distribution and immunoglobulin binding in relation to red cell age. Br. J. Haematol. 54, 209–219 (1983).

    CAS  Article  Google Scholar 

  26. 26

    Mollison, P.L., Contreras, M. & Engelfriet, C.P. ABO, Lewis, Ii and P groups. in Blood Transfusion in Clinical Medicine. 9th edn 155 (Blackwell Scientific Publishing, Oxford, 1993).

    Google Scholar 

  27. 27

    Hamano, K., Rawsthorne, M.A., Bushell, A.R., Morris, P.J. & Wood, K.J. Evidence that the continued presence of the organ graft and not peripheral donor microchimerism is essential for maintenance of tolerance to alloantigen in vivo in anti-CD4 treated recipients. Transplantation 62, 856–860 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Morecki, S., Leshem, B., Eid, A. & Slavin, S. Alloantigen persistence in induction and maintenance of transplantation tolerance. J. Exp. Med. 165, 1468–1480 (1987).

    CAS  Article  Google Scholar 

  29. 29

    Erikson, J., Radic, M.Z., Camper, SA., Hardy, R.R., Carmack, C. & Weigert, M. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–334 (1991).

    CAS  Article  Google Scholar 

  30. 30

    Goodnow, C.C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    CAS  Article  Google Scholar 

  31. 31

    Chelvarajan, R.L., Gilbert, N.L. & Bondada, S. Neonatal murine B lymphocytes respond to polysaccharide antigens in the presence of IL-1 and IL-6. J. Immunol. 161, 3315–3324 (1998).

    CAS  Google Scholar 

  32. 32

    Luo, W., Fine, J., Garg, M., Kaplan, A.M. & Bondada, S. Interleukin-10 enhances immune responses to pneumococcal polysaccharides and sheep erythrocytes in young and aged mice. Cell Immunol. 195, 1–9 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Splawski, J.B. & Lipsky, P.E. Cytokine regulation of immunoglobulin secretion by neonatal lymphocytes. J. Clin. Invest. 88, 967–977 (1991).

    CAS  Article  Google Scholar 

  34. 34

    Galili, U. Interaction of the natural anti-Gal antibody with alpha-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol. Today 14, 480–482 (1993).

    CAS  Article  Google Scholar 

  35. 35

    Chen, C. et al. The site and stage of anti-DNA B-cell deletion. Nature 373, 252–255 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Hartley, S.B., Crosbie, J., Brink, R., Kantor, A.B., Basten, A. & Goodnow, C.C. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353, 765–769 (1991).

    CAS  Article  Google Scholar 

  37. 37

    Nemazee, D.A. & Burki, K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337, 562–566 (1989).

    CAS  Article  Google Scholar 

  38. 38

    Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 (1993).

    CAS  Article  Google Scholar 

  39. 39

    Radic, M.Z., Erikson, J., Litwin, S. & Weigert, M. B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177, 1165–1173 (1993).

    CAS  Article  Google Scholar 

  40. 40

    Tiegs, S.L., Russell, D.M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020 (1993).

    CAS  Article  Google Scholar 

  41. 41

    Hammarstrom, L. & Smith, CI. Development of anti-polysaccharide antibodies in asplenic children. Clin. Exp. Immunol. 66, 457–462 (1986).

    CAS  Google Scholar 

  42. 42

    Lang, J. & Nemazee, D. B cell clonal elimination induced by membrane-bound self-antigen may require repeated antigen encounter or cell competition. Eur. J. Immunol. 30, 689–696 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Wang, C., Sun, J., Sheil, A.G., McCaughan, G.W. & Bishop, G.A. A short course of methylprednisolone immunosuppression inhibits both rejection and spontaneous acceptance of rat liver allografts. Transplantation 72, 44–51 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Perico, N., Imberti, O., Bontempelli, M. & Remuzzi, G. Immunosuppressive therapy abrogates unresponsiveness to renal allograft induced by thymic recognition of donor antigens. J. Am. Soc. Nephrol. 5, 1618–1623 (1995).

    CAS  Google Scholar 

  45. 45

    Yamada, K. et al. Role of the thymus in transplantation tolerance in miniature swine. I. Requirement of the thymus for rapid and stable induction of tolerance to class I-mismatched renal allografts. J. Exp. Med. 186, 497–506 (1997).

    CAS  Article  Google Scholar 

  46. 46

    Noris, M. et al. Thymic microchimerism correlates with the outcome of tolerance-inducing protocols for solid organ transplantation. J. Am. Soc. Nephrol. 12, 2815–2826 (2001).

    CAS  Google Scholar 

  47. 47

    Nakafusa, Y., Goss, J.A. & Flye, M.W. Prevention by thymectomy of tolerance induced by intrathymic injection of donor splenocytes. Surgery 114, 183–189 (1993).

    CAS  Google Scholar 

  48. 48

    Mond, J.J., Lees, A. & Snapper, C.M. T cell-independent antigens type 2. Annu. Rev. Immunol. 13, 655–692 (1995).

    CAS  Article  Google Scholar 

  49. 49

    Holsapple, M.P., West, L.J. & Landreth, K.S. Species comparison of anatomical and functional immune system development. Birth Defects Res. Part B Dev. Reprod. Toxicol. 68, 321–334 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Lin, S.S. et al. The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts. Transplantation 70, 1667–1674 (2000).

    CAS  Article  Google Scholar 

Download references


We thank K. Wood and M. Sykes for discussion and advice, and P. Morris and R. Zhong for reading of our manuscript. This work was supported with funding from the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Ontario, and the Research Training Competition at The Hospital for Sick Children.

Author information



Corresponding author

Correspondence to Lori J West.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fan, X., Ang, A., Pollock-BarZiv, S. et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 10, 1227–1233 (2004).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing