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Sci. Transl. Med., Jan 2025, 17 (779) | https://doi.org/10.1126/scitranslmed.adn8130
CD154 blockade effectively controls antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients
Imran J Anwar 1†, Isabel DeLaura 1†, Joseph M Ladowski 1, Davide Schilirò 1, Qimeng Gao 1, Miriam Manook 1, Janghoon Yoon 1, Rafaela Belloni 1, Angela Park 1, Daniel J Schuster 1, Mingqing Song 1, Lin Lin 2, Alton B Farris 3, Diogo Magnani 4, Kyha Williams 1, Jean Kwun 1, Stuart J Knechtle 1
1Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
2Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA.
3Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4Nonhuman Primate Reagent Resource, UMass Chan Medical School, Worcester, MA 01605, USA.
*Corresponding authors: J.K.; S.J.K.
†These authors contributed equally to this work.
1Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
2Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA.
3Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4Nonhuman Primate Reagent Resource, UMass Chan Medical School, Worcester, MA 01605, USA.
*Corresponding authors: J.K.; S.J.K.
†These authors contributed equally to this work.
Abstract
Current desensitization and maintenance immunosuppression regimens for kidney transplantation in sensitized individuals show limited ability to control the posttransplant humoral response, resulting in high rates of antibody-mediated rejection (ABMR) and graft failure. Here, we showed that anti-CD154 monoclonal antibody (mAb)-based immunosuppression more effectively controlled allograft rejection and humoral rebound in a highly sensitized nonhuman primate kidney transplantation model compared with tacrolimus-based standard-of-care (SOC) immunosuppression. Desensitization with an anti-CD154 mAb (5C8) and a proteasome inhibitor led to decreased donor-specific antibodies (DSAs) and disruption of lymph node germinal centers with reduction of proliferating, memory, and class-switched B cells as well as T follicular helper cells. After transplant, the nonhuman primates maintained on 5C8-based immunosuppression had significantly better survival compared with those maintained on SOC immunosuppression (135.2 days versus 32.8 days, P = 0.013). The 5C8-treated group demonstrated better suppression of DSAs after transplant, more robust suppression of B cell populations, and better induction of regulatory T cells. Fewer infectious and welfare complications, including viral reactivation and weight loss, were also observed with 5C8-based immunosuppression compared with SOC immunosuppression. Therefore, anti-CD154 mAbs may improve kidney transplant outcomes through better control of posttransplant immune responses. The superior efficacy of anti-CD154 mAb-based immunosuppression over tacrolimus-based SOC seen in this highly sensitized NHP transplant model suggests that anti-CD154 mAbs could potentially be used to desensitize and treat highly sensitized patients receiving kidney transplantation.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-01-03)
- 국외 연구진
- 의약학 > 면역의학
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