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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 724-736 |
| Number of pages | 13 |
| Journal | American Journal of Transplantation |
| Volume | 19 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by U19AI051731 (awarded to S.J.K.), part of the NIH NHP Transplantation Tolerance Cooperative Study Group sponsored by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. We would like to gratefully acknowledge the YNPRC (Yerkes National Primate Research Center) staff and the expert assistance of Dr. Elizabeth Strobert and Dr. Joe Jenkins for animal care; Pathology and histology support of Prachi Sharma and Deepa M. Kodandera. We would like to acknowledge the Emory Transplant Center biorepository for a weekly viral monitoring. Anti-CD4mAb, anti-CD8mAb, and anti-CD40mAb (2C10R4) used in this study were produced and provided by the Non-human Primate Reagent Resource (5R24OD010976, 1U24AI126683). C.K.B. received grant support by the Austrian Science Fund (FWF): project J3414 and a research stipend by the Austrian Society of Surgery.
Funding Information:
This work was supported by U19AI051731 (awarded to S.J.K.), part of the NIH NHP Transplantation Tolerance Cooperative Study Group sponsored by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. We would like to gratefully acknowledge the YNPRC (Yerkes National Primate Research Center) staff and the expert assistance of Dr. Elizabeth Strobert and Dr. Joe Jenkins for animal care; Pathology and histology support of Prachi Sharma and Deepa M. Kodandera. We would like to acknowledge the Emory Transplant Center biorepository for a weekly viral monitoring. Anti‐ CD4mAb, anti‐CD8mAb, and anti‐CD40mAb (2C10R4) used in this study were produced and provided by the Non‐human Primate Reagent Resource (5R24OD010976, 1U24AI126683). C.K.B. received grant support by the Austrian Science Fund (FWF): project J3414 and a research stipend by the Austrian Society of Surgery.
Publisher Copyright:
© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons
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
