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High antigen levels do not preclude B‐cell tolerance induction to α1,3‐Gal via mixed chimerism
Author(s) -
Haspot Fabienne,
Bardwell Philip D.,
Zhao Guiling,
Sykes Megan
Publication year - 2008
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/j.1399-3089.2008.00487.x
Subject(s) - epitope , antibody , b cell , immunology , bone marrow , biology , monoclonal antibody , immune tolerance , transplantation , total body irradiation , t cell , antigen , cell , microbiology and biotechnology , immune system , medicine , cyclophosphamide , genetics , chemotherapy
Background: Studies of bone marrow transplantation (BMT) from wild‐type mice or rats to α1,3‐galactosyltransferase (GalT) knockout mice have demonstrated that induction of mixed chimerism tolerizes not only T cells, but also natural antibody‐producing B cells, even across xenogeneic barriers. Given that rodent cells express lower levels of the αGal epitope than the more clinically relevant porcine species, the consequences of exposure to cells expressing high levels of αGal on the ability to induce B‐cell tolerance are unknown. Methods: The effects on chimerism and anti‐αGal B‐cell tolerance of an i.p. injection of 10 9 porcine RBC were evaluated in GalT knockout mice receiving wild‐type allogeneic BMT after non‐myeloablative conditioning with T‐cell depleting monoclonal antibodies, thymic irradiation, and low‐dose total body irradiation. Results: Achievement of mixed chimerism and tolerance of anti‐αGal‐producing B cells was not affected by exposure to high‐density αGal at the time of BMT. The absence of induced anti‐αGal or anti‐pig antibody responses in conditioned control mice suggested that the B‐cell xeno‐response to pig is T‐cell‐dependent. Conclusion: High αGal density on pig cells might not preclude the ability to achieve tolerance of pre‐existing αGal‐reactive human B cells via induction of mixed chimerism. This strategy has the potential to induce B‐cell tolerance to non‐αGal epitopes, against which natural antibodies have been found in the sera of healthy humans.