Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 19, Issue 3, Pages 724-736Publisher
WILEY
DOI: 10.1111/ajt.15067
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
Categories
Funding
- Austrian Science Fund [J3414]
- National Institute of Allergy and Infectious Diseases [U19AI051731]
- National Institute of Diabetes and Digestive and Kidney Diseases
- Austrian Science Fund (FWF) [J3414] Funding Source: Austrian Science Fund (FWF)
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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.
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