Translation of Therapeutic Strategies to Modulate B Cell Reponses from Non-human Primate Models to Human Kidney Transplantation

Overview

Journal Front Transplant

Specialty General Surgery

Date 2024 Jul 12

PMID 38993890

Authors

Stuart Knechtle

Jean Kwun

Shengli Song

Annette Jackson

Kitza Williams

Scott Sanoff

Affiliations

Soon will be listed here.

Abstract

Using novel drugs targeting lymphocyte costimulation, cytokines, antibody, complement, and plasma cells, we have developed strategies in a non-human primate model to modulate the B cell response to incompatible kidney transplants. After more than two decades of research supported by mechanistic studies, this has resulted in clinically relevant approaches that are currently enrolling in clinical trials or preparing for such. In this manner, we aim to address the problems of HLA sensitization for very highly sensitized patients awaiting transplantation and the unmet need of effective treatment for antibody-mediated rejection.

References

Sriwattanakomen R, Xu Q, Demehin M, Shullo M, Mangiola M, Hickey G . Impact of carfilzomib-based desensitization on heart transplantation of sensitized candidates. J Heart Lung Transplant. 2021; 40(7):595-603. DOI: 10.1016/j.healun.2021.03.001. View

Sullivan H, Krummey S, Gebel H, Bray R, Jackson A . Physical Crossmatching vs Virtual Crossmatching: The end of an era? or Why give up a good thing?. Hum Immunol. 2020; 81(8):401-406. DOI: 10.1016/j.humimm.2020.06.009. View

Jordan S, Choi J, Vo A . Kidney transplantation in highly sensitized patients. Br Med Bull. 2015; 114(1):113-25. DOI: 10.1093/bmb/ldv013. View

Manook M, Kwun J, Burghuber C, Samy K, Mulvihill M, Yoon J . Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. Am J Transplant. 2017; 17(8):2055-2064. PMC: 5519442. DOI: 10.1111/ajt.14234. View

Choi A, Manook M, Olaso D, Ezekian B, Park J, Freischlag K . Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization. Front Immunol. 2021; 12:694763. PMC: 8226120. DOI: 10.3389/fimmu.2021.694763. View

Otten H, Verhaar M, Borst H, van Eck M, van Ginkel W, Hene R . The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation. Clin Exp Immunol. 2013; 173(3):536-43. PMC: 3949641. DOI: 10.1111/cei.12127. View

Tremblay S, Driscoll J, Rike-Shields A, Hildeman D, Alloway R, Girnita A . A prospective, iterative, adaptive trial of carfilzomib-based desensitization. Am J Transplant. 2019; 20(2):411-421. PMC: 7872208. DOI: 10.1111/ajt.15613. View

Joher N, Matignon M, Grimbert P . HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers. Front Immunol. 2021; 12:688301. PMC: 8173048. DOI: 10.3389/fimmu.2021.688301. View

Schroder P, Schmitz R, Fitch Z, Ezekian B, Yoon J, Choi A . Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Kidney Int. 2020; 99(1):161-172. PMC: 7785689. DOI: 10.1016/j.kint.2020.08.020. View

10.

Song S, Manook M, Kwun J, Jackson A, Knechtle S, Kelsoe G . A cell-based multiplex immunoassay platform using fluorescent protein-barcoded reporter cell lines. Commun Biol. 2021; 4(1):1338. PMC: 8617053. DOI: 10.1038/s42003-021-02881-w. View

11.

McCarthy K, Watanabe A, Kuraoka M, Do K, McGee C, Sempowski G . Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires. Immunity. 2018; 48(1):174-184.e9. PMC: 5810956. DOI: 10.1016/j.immuni.2017.12.009. View

12.

Schmitz R, Fitch Z, Schroder P, Choi A, Manook M, Yoon J . C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates. Nat Commun. 2021; 12(1):5456. PMC: 8443599. DOI: 10.1038/s41467-021-25745-7. View

13.

Knechtle S, Shaw J, Hering B, Kraemer K, Madsen J . Translational impact of NIH-funded nonhuman primate research in transplantation. Sci Transl Med. 2019; 11(500). PMC: 7197021. DOI: 10.1126/scitranslmed.aau0143. View

14.

Sellares J, de Freitas D, Mengel M, Reeve J, Einecke G, Sis B . Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2011; 12(2):388-99. DOI: 10.1111/j.1600-6143.2011.03840.x. View

15.

Filippone E, Farber J . Histologic Antibody-mediated Kidney Allograft Rejection in the Absence of Donor-specific HLA Antibodies. Transplantation. 2021; 105(11):e181-e190. DOI: 10.1097/TP.0000000000003797. View

16.

Sullivan H, Gebel H, Bray R . Understanding solid-phase HLA antibody assays and the value of MFI. Hum Immunol. 2017; 78(7-8):471-480. PMC: 8663030. DOI: 10.1016/j.humimm.2017.05.007. View

17.

Wehmeier C, Karahan G, Heidt S . HLA-specific memory B-cell detection in kidney transplantation: Insights and future challenges. Int J Immunogenet. 2020; 47(3):227-234. PMC: 7317812. DOI: 10.1111/iji.12493. View

18.

Sullivan H, Liwski R, Bray R, Gebel H . The Road to HLA Antibody Evaluation: Do Not Rely on MFI. Am J Transplant. 2017; 17(6):1455-1461. PMC: 8663029. DOI: 10.1111/ajt.14229. View

19.

Hariharan S, Israni A, Danovitch G . Long-Term Survival after Kidney Transplantation. N Engl J Med. 2021; 385(8):729-743. DOI: 10.1056/NEJMra2014530. View

20.

Anwar I, Ezekian B, DeLaura I, Manook M, Schroder P, Yoon J . Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model. Am J Transplant. 2022; 22 Suppl 4:1-11. PMC: 9722597. DOI: 10.1111/ajt.17208. View