Premium
Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients
Author(s) -
Burghuber Christopher K.,
Manook Miriam,
Ezekian Brian,
Gibby Adriana C.,
Leopardi Frank V.,
Song Minqing,
Jenks Jennifer,
Saccoccio Frances,
Permar Sallie,
Farris Alton B.,
Iwakoshi Neal N.,
Kwun Jean,
Knechtle Stuart J.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15067
Subject(s) - medicine , bortezomib , belatacept , germinal center , blockade , desensitization (medicine) , transplantation , kidney transplantation , immunology , oncology , urology , multiple myeloma , antibody , b cell , receptor , kidney transplant
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.