Alloantibody-mediated injury remains a major challenge for the improvement of long-term graft survival and there is no effective therapy to prevent alloantibody generation post-transplant. The Notch pathway is a major cell-cell signaling pathway that plays a crucial role in cell development and fate. In the immune system, Notch2 is differentially expressed on B cell subsets and is known to be critical for marginal zone B cells (MZB) differentiation and positioning in secondary lymphoid organs. However, little is known about the role of Notch2 in alloantibody production post-transplantation.

Herein, using a fully MHC-mismatch cardiac and skin transplant model (BALB/c into C57BL/6J), we report that Notch2^fl/flCD19-Cre (Notch2cKO) recipients do not develop allo-specific antibodies both short- and long-term (day 8 and >120 after transplant, respectively) . This was consistent with our previous findings that transient administration of anti-Notch2 antibody (day 0, 3, 5, 7, 9, 11) in a similar cardiac transplant model completely suppressed alloantibody production. Interestingly, this attenuation of alloantibody production in Notch2cKO mice is associated with less plasma cells (B220^loCD138⁺; 0.038±0.16% vs. 0.34±0.02 on controls, p<0.01), germinal center cells (GL7⁺Fas⁺; 0.27±0.054% vs 1.1±0.25, p=0.19), T follicular helper cells (Tfh; CD4⁺PD1⁺CXCR5⁺; 4.66±0.29% vs 5.83±0.26, p=0.022) and MZB cells (Figure below).

These data indicate that Notch2 signaling is critical for the alloantibody generation post-transplantation and suggest that selective Notch2 blockade might be a promising therapeutic strategy to prevent the antibody-mediated injury so resistant to current therapy.

CITATION INFORMATION: Murakami N, Magee C, Borges T, Azzi J, Riella L. Selective Deletion of Notch2 on B Cells Abrogates Alloantibody Production in Fully MHC-Mismatched Cardiac and Skin Transplant Models. Am J Transplant. 2016;16 (suppl 3).

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