Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Academic Article uri icon

Overview

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.

publication date

  • September 17, 2018

Research

keywords

  • Abatacept
  • Antibodies, Monoclonal
  • Bortezomib
  • CD40 Antigens
  • Graft Rejection
  • Graft Survival
  • Kidney Transplantation

Identity

PubMed Central ID

  • PMC7185755

Scopus Document Identifier

  • 85053444237

Digital Object Identifier (DOI)

  • 10.1111/ajt.15067

PubMed ID

  • 30102844

Additional Document Info

volume

  • 19

issue

  • 3