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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Lori J West.

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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). https://doi.org/10.1038/nm1126

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