Ibrutinib suppresses alloantibody responses in a mouse model of allosensitization

Background: Ibrutinib is a Bruton's tyrosine Kinase (BTK) antagonist that inhibits B cell receptor (BCR) signaling. Complete BTK deficiency is associated with absence of B-cells. Ibrutinb is currently approved by FDA for treatment of B-cell malignancies, including Waldenstrom macroglobulinaemia. We recently carried out studies to determine if ibrutinib could modify alloantibody responses. Materials and methods: A mouse model of allogenic sensitization using a C57BL/6 mouse as the recipient of a skin allograft from an HLA-A2 transgenic mouse was utilized to examine the effects of ibrutinib on alloantibody responses and B cell effector functions. Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay. Splenic T and B cell subsets and plasma cells were analyzed in flow cytometry. Results: Control mice developed peak levels of DSA IgM at day 14 PTx while the ibrutinib treated mice had significantly lower levels of DSA IgM (p = 0.0047). Control mice developed HLA.A2-specific IgG antibodies at day 14 (230 +/- 60 MFI) and reached peak levels at day 21 (426 +/- 61 MFI). In contrast, mice in the treatment group had low levels of HLA.A2-specific IgG at day 14 (109 +/- 59 MFI, p = 0.004) and day 21 (241 +/- 86 MFI, p = 0.003). FACS analysis found a reduction of B220(+) or CD19(+) B cell population (p < 0.05). In addition, ibrutinib attenuated recall DSA IgG responses to re-sensitization (p < 0.05) and reduced CD38(+) CD138(+) plasma cells (p < 0.05) in the spleens. Conclusions: Ibrutinib is effective in suppressing alloantibody responses through blocking BTK-mediated BCR signaling, leading to reduction of B cells and short-lived plasma cells in the spleens. Use of ibrutinib may provide benefits to HLA-sensitized transplant patients for alloantibody suppression.