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Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance¹

Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL 60637

The impact of memory B cells and alloantibodies on the ability to induce transplantation tolerance has not been elucidated. We have developed a murine heart transplant model that isolates the contributions of functional memory B cells from memory T cells in allograft rejection. Memory 3-83 B cells with dual specificity for H-2K^k and H-2K^b were generated in 3-83 Igi BCR knockin (BALB/c background) mice by the transplantation of C3H (H-2K^k) hearts in the absence of immunosuppression. To test the effect of functional memory 3-83 B cells, C3H-primed 3-83 Igi recipients were challenged with C57BL/6 hearts (H-2K^b) at 60–90 days post-C3H heart transplant and treated with anti-CD154 mAbs. Despite immunosuppression, the C57BL/6 hearts were acutely rejected within 10–13 days and graft rejection was associated with increased frequencies of C57BL/6-specific IFN--producing T cells. Histology revealed significant numbers of infiltrating T cells, consistent with acute T cell-mediated rejection. The resistance to tolerance induction was dependent on the synergistic effects of memory 3-83 B cells and alloantibodies, whereas memory T cells are not necessary. We conclude that the combined effects of functional memory B cells and alloantibodies prevent anti-CD154-mediated graft acceptance by facilitating the CD40-CD154-independent activation of alloreactive T cells. This study provides insight into the potential ability of memory B cells and alloantibodies to prevent anti-CD154-mediated graft acceptance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant 2R56AI043631 and a R01 AI052464 to A.S.C. and a minority supplement to A.M.B.

² Address correspondence and reprint requests to Dr. Anita S. Chong, Section of Transplantation, Department of Surgery, 5841 S. Maryland Avenue, Room -J547, MC5026, Chicago, IL 60637. E-mail address: achong{at}surgery.bsd.uchicago.edu

³ Abbreviations used in this paper: MST, mean survival time; IVIg, i.v. Ig therapy; Tg, transgenic.