title: Memory alloreactive B cells and alloantibodies prevent anti-CD154-mediated allograft acceptance.
abstract: 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-gamma-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.
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Audrea M
authors.initials: AM
authors.lastname: Burns
authors.forename: Lianli
authors.initials: L
authors.lastname: Ma
authors.forename: Yijin
authors.initials: Y
authors.lastname: Li
authors.forename: Dengping
authors.initials: D
authors.lastname: Yin
authors.forename: JiKun
authors.initials: J
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Anita S
authors.initials: AS
authors.lastname: Chong
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D055879:Gene Knock-In Techniques; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007518:Isoantibodies / Q000096:biosynthesis / Q000378:metabolism*; D007519:Isoantigens / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016042:Transplantation, Heterotopic
chemical_list: D000911:Antibodies, Monoclonal; D007518:Isoantibodies; D007519:Isoantigens; D023201:CD40 Ligand