Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients

Christopher K. Burghuber, Miriam Manook, Brian Ezekian, Adriana C. Gibby, Frank V. Leopardi, Minqing Song, Jennifer Jenks, Frances Saccoccio, Sallie Permar, Alton B. Farris, Neal N. Iwakoshi, Jean Kwun, Stuart J. Knechtle

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy–mediated DSA reductions approached statistical significance (P =.07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P =.073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P =.020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

Original languageEnglish (US)
Pages (from-to)724-736
Number of pages13
JournalAmerican Journal of Transplantation
Volume19
Issue number3
DOIs
StatePublished - Mar 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

  • alloantibody
  • animal models: nonhuman primate
  • basic (laboratory) research/science
  • desensitization
  • immunosuppressant - fusion proteins and monoclonal antibodies: costimulation molecule specific
  • immunosuppression/immune modulation
  • kidney transplantation/nephrology
  • plasma cells

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