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-2Kk and H-2Kb were generated in 3-83 Igi BCR knockin (BALB/c background) mice by the transplantation of C3H (H-2Kk) 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-2Kb) 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-γ-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.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…Indeed, the accumulation of CD4 + and CD8 + T cells in the allograft was further reduced in the combination therapy group compared with monotherapy groups, and approached numbers that were comparable to naive tolerant allografts ( Figure 6A). We also tested whether FTY720 plus CTLA4-Ig reduced donor-specific infiltrating T cells by using sensitized mice that harbored, from the time of donor spleen cell sensitization, a tracer population of donor-reactive T cell receptor-transgenic TCR75 cells (1,000-2,000 cells/mouse) with specificity for donor-derived peptide (K d [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] ) presented on recipient I-A b . We similarly observed that the combination FTY720 plus CTLA4-Ig significantly decreased the numbers of TCR75 cells (which were predominantly CD44 + CD62L -) infiltrating the allografts compared with CTLA4-Ig monotherapy ( Figure 6B).…”

“…Secondly, this model does not define the effects of CTLA4-Ig on memory T cells the way that an adoptive transfer model would. However, we consider the sensitization of B and T cells and the presence of low levels of circulating antibodies a strength of this model, as we have previously shown that DSA can promote antigen uptake through opsonization, enhance antigen-presenting cell (APC) activation, and alter the signals provided by APCs to memory T cells (8,56). Indeed, we observed that the efficacy of CTLA4-Ig was inferior in recipients that were more recently sensitized and harbored higher levels of DSA.…”

Alloantibodies Prevent the Induction of Transplantation Tolerance by Enhancing Alloreactive T Cell Priming

“…Indeed, deliberate sensitization or infection of rodent recipients, resulting in high frequencies of memory alloreactive CD4 + and CD8 + T cells, leads to an acquired resistance to tolerance induction (3)(4)(5)(6). In addition, we recently reported that memory alloreactive B cells alone, or in combination with alloantibodies, prevented the acquisition tolerance in anti-CD154-treated recipients (7). Thus, the presence of memory B cells and alloantibodies, or T cells, can independently resist tolerance induction.…”

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

“…The molecular and cellular mechanisms by which B cells regulate the immune response are currently not well understood. Apart from the well-known Ab-mediated mechanisms, Ab-independent functions such as Ag presentation and cytokine production play a crucial role in B cell-mediated immunopathology (47)(48)(49)(50)(51). Alternatively, regulatory B lymphocytes can foster tolerance induction through a number of mechanisms, including the production of immunosuppressive cytokines and expansion of regulatory T cells (52)(53)(54)(55).…”