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Impact of Desensitization Strategies with Proteosome Inhibition and Costimulation Blockade on Xenoreactive Humoral Responses

B. P. Lovasik1, A. J. Matar1, D. A. Faber1, D. V. Mathews1, C. P. Breeden1, S. C. Kim1, A. J. Tector2, A. B. Adams1

1Emory University School of Medicine, Atlanta, GA, 2University of Miami, Miami, FL

Meeting: 2020 American Transplant Congress

Abstract number: A-280

Keywords: Antibodies, Highly-sensitized, Sensitization, Xenoreactive antibodies

Session Information

Session Name: Poster Session A: Xenotransplantation

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

 Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: “Delayed” antibody-mediated xenograft rejection is the one of the most important obstacles to clinical application of pig organ xenografts. The aim of this study was to assess the impact of a structured desensitization regimen including proteasome inhibition and next-generation costimulation blockade on xenoreactive antibodies.

*Methods: Rhesus macaques with moderate-high pre-treatment xenoreactive antibody titers (N=2) were selected. Recipients received biweekly carfilzomib 20mg/m2), anti-CD154 (20mg/kg) every other week, and CD4 T cell and B cell depletion. Bone marrow was acquired to assess plasma cell depletion in response to proteasome inhibition. A flow cytometry-based xenoreactive crossmatch assay was performed to assess levels of circulating xenoreactive antibodies.

*Results: The desensitization regimen resulted in a >50% depletion of CD38+CD27+ bone marrow plasma cells (Panel A); these changes were progressive over the duration of the desensitization treatment period. The desensitization strategy and plasma cell depletion resulted in a progressive reduction in anti-pig IgG antibodies (Panel B); in both cases, anti-pig antibody titers were reduced from a level consistent with a high-titer control NHP to a level approaching a low-titer NHP. There were no adverse effects or toxicities associated with the desensitization protocol, though low level CMV viremia but not CMV associated disease was noted.

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*Conclusions: A structured desensitization regimen including proteasome inhibition and costimulation blockade results in plasma cell depletion and resultant reduction in circulating xenoreactive anti-pig IgG antibodies. This desensitization regimen has promise for pig-to-NHP xenotransplant models.

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To cite this abstract in AMA style:

Lovasik BP, Matar AJ, Faber DA, Mathews DV, Breeden CP, Kim SC, Tector AJ, Adams AB. Impact of Desensitization Strategies with Proteosome Inhibition and Costimulation Blockade on Xenoreactive Humoral Responses [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/impact-of-desensitization-strategies-with-proteosome-inhibition-and-costimulation-blockade-on-xenoreactive-humoral-responses/. Accessed May 10, 2025.

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