Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant

Author:

Manook Miriam1ORCID,Olaso Danae1ORCID,Anwar Imran J.1ORCID,Yoon Janghoon1ORCID,Delaura Isabel1ORCID,Bae Yeeun1ORCID,Moris Dimitrios1,Shaw Brian1ORCID,Song Mingqing1,Farris Alton B.2ORCID,Jackson Annette1ORCID,Kwun Jean1ORCID,Knechtle Stuart1ORCID

Affiliation:

1. Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

2. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.

Abstract

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m 2 ) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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