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Author Notes:

Correspondence: Stuart J. Knechtle, 330 Trent Dr, DUMC Box 3512, Durham, NC 27710; e-mail: stuart.knechtle@duke.edu.

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The authors acknowledge Frank Leopardi (Duke University) for assisting in animal surgeries and procedures, Mingqing Song (Duke University) for supporting tissue preparation and basic histologic support, Drew Roenneburg (University of Wisconsin-Madison) for immunohistochemistry, and the Emory Transplant Center biorepository and Duke Transplant Center substrate core for their weekly viral monitoring.

Belatacept was initially provided by BMS and purchased later.

The authors thank veterinary supports from Yerkes National Primate Research Center and Duke Laboratory Animal Resources, especially for the expert assistance of Elizabeth Strobert and Joe Jenkins (Yerkes National Primate Research Center) and Kyha Williams and Felicitas Smith (Duke Laboratory Animal Resources).

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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Research Funding:

This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (U19AI051731) (S.J.K.).

Anti-CD40mAb (2C10) used in this study was produced and provided by the Non-human Primate Reagent Resource (National Institutes of Health grants 5R24OD010976 from the Office of the Director/Office of Research Infrastructure Programs and 1U24AI126683 from the National Institute of Allergy and Infectious Diseases).

Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates

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Journal Title:

Blood Advances

Volume:

Volume 1, Number 24

Publisher:

, Pages 2115-2119

Type of Work:

Article | Final Publisher PDF

Abstract:

The detrimental effects of donor-directed antibodies in sensitized transplant patients remain a difficult immunologic barrier to successful organ transplantation. Antibody removal is often followed by rebound. Proteasome inhibitors (PIs) deplete antibody-producing plasma cells (PCs) but have shown marginal benefit for desensitization. In an allosensitized nonhuman primate (NHP) model, we observed increased germinal center (GC) formation after PI monotherapy, suggesting a compensatory PC repopulation mediated via GC activation. Here we show that costimulation blockade (CoB) targets GC follicular helper T (Tfh) cells in allosensitized NHPs. Combined PI and CoB significantly reduces bone marrow PCs (CD19+CD20−CD38+), Tfh cells (CD4+ICOS+PD-1hi), and GC B cells (BCL-6+CD20+); controls the homeostatic GC response to PC depletion; and sustains alloantibody decline. Importantly, dual PC and CoB therapy prolongs rejection-free graft survival in major histocompatibility complex incompatible kidney transplantation without alloantibody rebound. Our study illustrates a translatable desensitization method and provides mechanistic insight into maintenance of alloantibody sensitization.

Copyright information:

© 2017 by The American Society of Hematology

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