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

Am J Transplant. 2019 Mar;19(3):724-736. doi: 10.1111/ajt.15067. Epub 2018 Sep 17.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept / pharmacology*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Bortezomib / pharmacology*
  • CD40 Antigens / antagonists & inhibitors*
  • CD40 Antigens / immunology
  • Drug Therapy, Combination
  • Graft Rejection / etiology
  • Graft Rejection / pathology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • Immunosuppressive Agents / pharmacology
  • Kidney Transplantation / adverse effects*
  • Macaca mulatta
  • Male
  • Transplant Recipients


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CD40 Antigens
  • Immunosuppressive Agents
  • Bortezomib
  • Abatacept