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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Burghuber, CK; Manook, M; Ezekian, B; Gibby, AC; Leopardi, FV; Song, M; Jenks, J; Saccoccio, F; Permar, S; Farris, AB; Iwakoshi, NN; Kwun, J; Knechtle, SJ

Published Date

  • March 2019

Published In

Volume / Issue

  • 19 / 3

Start / End Page

  • 724 - 736

PubMed ID

  • 30102844

Pubmed Central ID

  • 30102844

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

International Standard Serial Number (ISSN)

  • 1600-6135

Digital Object Identifier (DOI)

  • 10.1111/ajt.15067

Language

  • eng