Cutting Edge: CTLA-4Ig Inhibits Memory B Cell Responses and Promotes Allograft Survival in Sensitized Recipients

Abstract

Sensitized recipients with pre-transplant donor-specific antibodies (DSA) are at higher risk for antibody-mediated rejection (AMR) than non-sensitized recipients, yet little is known about the properties of memory B cells that are central to the recall alloantibody responses. Using cell enrichment and MHC Class I tetramers, C57BL/6 mice sensitized with BALB/c splenocytes were shown to harbor H-2Kd-specific IgG+ memory B cells with a post-GC phenotype (CD73+CD273+CD38hiCD138−GL7−). These memory B cells adoptively transferred in naïve mice without memory T cells recapitulated class-switched recall alloantibody responses. During recall, memory H-2Kd-specific B cells preferentially differentiated into antibody-secreting cells (ASCs), whereas in primary response, H-2Kd-specific B cells differentiated into germinal center (GC) cells. Finally, our studies revealed that despite fundamental differences in alloreactive B cell fates in sensitized versus naive recipients, CTLA-4Ig was unexpectedly effective at constraining B cell responses and heart allograft rejection in sensitized recipients.

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

“…Despite the relatively low frequencies of 2W:I-A b -reactive CD4 + and OVA:K b -reactive CD8 + memory cells, transplantation of B/c heart grafts into the allosensitized B/6 recipients treated with continuous CTLA4-Ig resulted in only approximately 50% of the grafts surviving for more than 60 days after transplantation, in contrast to 100% graft acceptance in comparably treated naive recipients ( Figure 2, A and B). The rejection in CTLA4-Ig-treated sensitized recipients occurred even though alloantibody production was inhibited ( Figure 2C), consistent with our previous observations (16). Because rejection in this transplant model is mediated primarily by T cells, we investigated the effects of CTLA4-Ig in sensitized recipients by quantifying the frequency of donor-reactive IFN-γ-producing cells.…”

“…We and others have reported that CTLA4-Ig inhibits early T cell-dependent alloantibody responses as well as recall responses (15)(16)(17)(18). In this study, we extend those observations by characterizing the impact of extended CTLA4-Ig treatment on graft-reactive memory T cell responses.…”

“…Similarly, we observed that FTY720 monotherapy permitted an increase in alloantibody production in sensitized recipients after B/c heart transplantation ( Figure 5A). However, the combination of FTY720 with CTLA4-Ig prevented this recall DSA response, comparable to CTLA4-Ig monotherapy, thus confirming that FTY720 did not abrogate the beneficial effects of CTLA4-Ig on memory B cell responses and alloantibody production (16).…”

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept

“…While our numbers preclude any concrete conclusions, larger clinical trials have documented a persistent improvement in recipient allograft function over years in belatacept-treated individuals compared to those treated with cyclosporine (21), as well as a lack of donor-specific HLA antibody (13). While it is conceivable that the improved adherence resulting from an infused immunosuppressive agent and possibly greater exposure to MPA compared to cyclosporine-based maintenance regimens, further preclinical and recent clinical studies have demonstrated a potent inhibitory effect of blockade of CD28/CD80/CD86 pathway on B cell function (22). These features of this agent are of utmost clinical relevance as long-term antibody injury is a critical contributor to late kidney allograft failure.…”

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans

“…Furthermore, plasma cells express little to no CD19 or B cell receptor, making the identification of antigen-specific plasma cells by cell-surface expression and flow cytometry extremely challenging. Thus, an alternative approach has been developed to detect the frequency of plasma cells secreting MHC-specific antibodies using an ELISpot assay that utilizes immobilized anti-IgG and biotinylated MHC monomers 81,102,103 . Sicard et al 103 reported that the frequency of plasma cells posttransplantation was increased ~10 4 -fold in the spleen and ~10 3 -fold in the bone-marrow, in contrast to the plasma cells generated following viral infections that were predominantly enriched in the bone marrow.…”