Background: Sensitized recipients have lower rates of transplantation and poorer outcomes. We and others have reported that the delayed administration of CTLA4-Ig can disrupt fully-established B cell germinal center (GC) responses and prevent the production of post-GC plasma cells, while Bortezomib has been reported to deplete plasma cells. When used individually, these drugs often lead to an incomplete reversal of established alloantibody responses, especially in sensitized recipients with high titers of circulating donor-specific antibodies (DSA). Here we tested the ability of Bortezomib in combination with CTLA4-Ig to reverse established alloantibody responses in skin-allograft sensitized recipients and their impact on bone marrow resident plasma cells.

Materials & Method: C57BL/6 female mice were sensitized with BALB/c donor splenocytes or skin grafts and challenged with BALB/c skin grafts 10 weeks later. Mice were treated with 2 doses of Bortezomib and CTLA4-Ig (2X/week). Bone marrow were harvested from both naïve and sensitized mice to analyze antibody secreting cell subsets. Submandibular blood collection was performed at 1-2 week intervals to measure DSA titers.

Results: Treatment with 2 doses of Bortezomib and CTLA4-Ig started from 14 days post allogeneic splenocyte immunization or skin transplantation rapidly reduced DSA in naive (p= .006) and presensitized recipients (p< .001). Furthermore, repeated Bortezomib (2 consecutive daily doses given every 2-4 weeks) in combination with CTLA4-Ig sequentially reduced DSA in sensitized recipients with persistent and high-titer preformed DSA (even when treatment was started at 5 weeks post-skin transplant). Finally, Bortezomib significantly deplete early (p= .014) and long lived (p= .005) bone marrow-resident plasma cells.

Conclusion: The ability of Bortezomib in combination with CTLA4-Ig to desensitized recipients with persisting high-titer preformed DSA is due to the preferential depletion by bortezomib of long-lived plasma cells in the bone marrow and the prevention of new plasma cells generation by CTLA4-Ig. These observations may explain our clinical observations of the efficacy of Bortezomib and Belatacept in controlling acute ABMR.

CITATION INFORMATION: Jain D., Young J., Yin D., Pelletier R., Chong A. CTLA4-Ig and Bortezomib Successfully Reverses Established DSA Responses in Allograft-Sensitized Recipients Am J Transplant. 2017;17 (suppl 3).

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