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

• Type of Material: Article
• Authors: Jean Kwun, Duke University; Christopher Burghuber, Emory University; Miriam Manook, Duke University; Brian Ezekian, Duke University; Jaeberm Park, Duke University; Janghoon Yoon, Duke University; John S. Yi, Duke University; Neal N. Iwakoshi, Emory University; Adriana Gibby, Emory University; Jung Joo Hong, Emory University; Alton B Farris III, Emory University; Allan D Kirk, Emory University; Stuart Knechtle, Emory University
• Language: English
• Date: 2017-11-14
• Publisher: American Society of Hematology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2017010991
• Title of Journal or Parent Work: Blood Advances
• ISSN: 2473-9529
• Volume: 1
• Issue: 24
• Start Page: 2115
• End Page: 2119
• Grant/Funding Information: 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).
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

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.