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BRIEF RESEARCH REPORT article

Front. Transplant.
Sec. Immunosuppression
Volume 3 - 2024 | doi: 10.3389/frtra.2024.1494455
This article is part of the Research Topic Strategies to Overcome HLA Sensitization in Kidney Transplantation View all articles

Immunoproteasome Inhibition Reduces Donor Specific Antibody Production and Cardiac Allograft Vasculopathy in a Mouse Heart Transplantation Model

Provisionally accepted
Allie Schwalb Allie Schwalb Imran John Anwar Imran John Anwar Isabel DeLaura Isabel DeLaura Joseph Ladowski Joseph Ladowski Janghoon Yoon Janghoon Yoon Rafaela Belloni Rafaela Belloni Mingqing Song Mingqing Song Carolyn Glas Carolyn Glas Jun Wang Jun Wang Stuart Knechtle Stuart Knechtle Jean Kwun Jean Kwun *
  • Duke University, Durham, United States

The final, formatted version of the article will be published soon.

    Objective: Cardiac Allograft Vasculopathy (CAV), a process of vascular damage accelerated by antibodymediated rejection (AMR), is one of the leading causes of cardiac transplant failure. Proteasome inhibitors (PIs) are utilized to treat AMR, however PI-associated toxicity limits their therapeutic utility.Novel immunoproteasome inhibitors (IPIs) have higher specificity for immune cells and have not been investigated for AMR in cardiac transplant patients. We sought to evaluate IPI effect on AMR in a murine cardiac transplant model.Fully MHC mismatched C57BL/6 to huCD52Tg heterotopic heart transplantations were performed. Recipients were treated with alemtuzumab (10µg, IP) on days -2, -1, 2, and 4 and anti-CD25mAb (PC61, 100µg, IP) on day 7 to accelerate AMR with or without IPI (ONX-0914,15mg/kg, SQ), administered on transplant day and three times a week thereafter.Results: Animals without IPI gradually developed post-transplant donor-specific antibody (DSA) and showed a significantly elevated DSA level compared to animals receiving IPI. (TFXM 48.86 vs. 14.17; p=0.0291, BFXM 43.53 vs. 6.114; p=0.0031). Accordingly, H&E staining of allograft showed reduced evidence of AMR with IPI compared to controls (P=0.0410). Notably, increased mortality was observed in the IPI treated group.This study demonstrated the ability of ONYX-0914, an IPI, to control post-transplant DSA production and the AMR development in a heart transplant model. However, IPI-resistant DSA production was also observed and increased mortality with IPI therapy raises concerns about potential toxicity. Further investigation is warranted to assess the utility and potential risk associated with the use of IPI as a post-transplant maintenance immunosuppression.

    Keywords: immunoproteasome, Antibody-mediated Rejection, Cav, regulatory T cells, Alloantibody

    Received: 10 Sep 2024; Accepted: 02 Dec 2024.

    Copyright: © 2024 Schwalb, Anwar, DeLaura, Ladowski, Yoon, Belloni, Song, Glas, Wang, Knechtle and Kwun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jean Kwun, Duke University, Durham, United States

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