Background Bruton tyrosine kinase (Btk) is specifically required for activation of the B-cell antigen receptor signaling pathway that contributes to the initiation and maintenance of B-cell immunity. In a mouse model of allo-sensitization using skin allografts, we have recently demonstrated that the Btk inhibitor ibrutinib is effective in suppressing alloantibody responses. The current study further investigates the B-cell subset changes induced by ibrutinib treatments.

Methods A mouse model of allosensitization to skin allograft (donor: C57BL/j6-tg-HLA.A2 and recipient: C57BL/j6) was employed with or without ibrutinib treatment (20mg/kg/day). Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay. Splenic T and B cell subsets and bone marrow B/plasma cells were analyzed in flow cytometry.

Results Ibrutinib treatment significantly reduced donor-specific IgM (Day 14: 7.7+1.6 mean fluorescent intensity [MFI] v.s Control 21+2.1 MFI, p=0.004) and IgG (Day 21: 241+86 MFI v.s. Control 426+61 MFI, p=0.003). Flow-cytometric analysis of splenic lymphocytic cells procured at Day 6 post-skin grafting shows there is no significant change in major lymphocytic subsets of CD3⁺ (pan T), CD4⁺ (T-helper), CD8⁺, NK1.1⁺ (NK cell), and CD11b⁺ (monocyte/macrophages). A moderate but significant reduction by ibrutinib treatments, however, is found at B220⁺ (CD45R, p=0.014 vs. control), CD19⁺ (p=0.026) and activation marker GL7⁺ (B220⁺/GL7⁺, p=0.007 vs. control) B-cells. Furthermore, a reduction by ibrutinib treatment of CD38^dimCD138⁺ plasma cells is observed (p=0.027 vs. control). No change by ibrutinib treatment is found in B-cell subsets regarding co-expression of CD20, CD23, CD93, sIgM and sIgD.

Conclusion Our data demonstrate that ibrutinib can specifically target B-cell subsets, therefore contributing to alloantibody suppression. Strategic use of Btk inhibition, alone or in combination with other immune suppressants may provide additional benefit to organ transplant patients, especially those in high risk of antibody mediated rejection.

CITATION INFORMATION: Chai N.-N, Kim I, Jordan S, Klein A, Wu G. Alloantibody Suppression by Bruton Tyrosine Kinase Antagonist Ibrutinib Is Associated with a Moderate Splenic B-Cell Reduction. Am J Transplant. 2016;16 (suppl 3).

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