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

Jean Kwun, Christopher Burghuber, Miriam Manook, Brian Ezekian, Jaeberm Park, Janghoon Yoon, John S. Yi, Neal Iwakoshi, Adriana Gibby, Jung Joo Hong, Alton B. Farris, Allan D. Kirk, Stuart J. Knechtle

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 antibodyproducing 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 repopulationmediated via GCactivation.Herewe showthat costimulation blockade (CoB) targetsGCfollicularhelperT(Tfh) cells in allosensitized NHPs. Combined PI and CoB significantly reduces bone marrow PCs (CD19+CD202CD38+), Tfh cells (CD4+ICOS+PD-1hi), and GC B cells (BCL-61CD201); 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.

Original languageEnglish (US)
Pages (from-to)2115-2119
Number of pages5
JournalBlood Advances
Volume1
Issue number24
DOIs
StatePublished - Nov 14 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (U19AI051731) (S.J.K.). Authorship Contribution: J.K. designed experiments, performed surgical procedures and cared for experimental macaques, conducted in vitro experiments, analyzed and interpreted data, and prepared the

Funding Information:
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). 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).

Publisher Copyright:
© 2017 by The American Society of Hematology.

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