@article{fbdaaeb8ff444f9d9b5c2249f250356d,
title = "Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates",
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.",
author = "Jean Kwun and Christopher Burghuber and Miriam Manook and Brian Ezekian and Jaeberm Park and Janghoon Yoon and Yi, {John S.} and Neal Iwakoshi and Adriana Gibby and Hong, {Jung Joo} and Farris, {Alton B.} and Kirk, {Allan D.} and Knechtle, {Stuart J.}",
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: {\textcopyright} 2017 by The American Society of Hematology.",
year = "2017",
month = nov,
day = "14",
doi = "10.1182/bloodadvances.2017010991",
language = "English",
volume = "1",
pages = "2115--2119",
journal = "Blood Advances",
issn = "2473-9529",
number = "24",
}