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

Publication ,  Journal Article
Burghuber, CK; Manook, M; Ezekian, B; Gibby, AC; Leopardi, FV; Song, M; Jenks, J; Saccoccio, F; Permar, S; Farris, AB; Iwakoshi, NN; Kwun, J ...
Published in: Am J Transplant
March 2019

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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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2019

Volume

19

Issue

3

Start / End Page

724 / 736

Location

United States

Related Subject Headings

  • Transplant Recipients
  • Surgery
  • Male
  • Macaca mulatta
  • Kidney Transplantation
  • Immunosuppressive Agents
  • Graft Survival
  • Graft Rejection
  • Drug Therapy, Combination
  • CD40 Antigens
 

Citation

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Burghuber, C. K., Manook, M., Ezekian, B., Gibby, A. C., Leopardi, F. V., Song, M., … Knechtle, S. J. (2019). Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant, 19(3), 724–736. https://doi.org/10.1111/ajt.15067
Burghuber, Christopher K., Miriam Manook, Brian Ezekian, Adriana C. Gibby, Frank V. Leopardi, Minqing Song, Jennifer Jenks, et al. “Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients.Am J Transplant 19, no. 3 (March 2019): 724–36. https://doi.org/10.1111/ajt.15067.
Burghuber CK, Manook M, Ezekian B, Gibby AC, Leopardi FV, Song M, et al. Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant. 2019 Mar;19(3):724–36.
Burghuber, Christopher K., et al. “Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients.Am J Transplant, vol. 19, no. 3, Mar. 2019, pp. 724–36. Pubmed, doi:10.1111/ajt.15067.
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. Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant. 2019 Mar;19(3):724–736.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2019

Volume

19

Issue

3

Start / End Page

724 / 736

Location

United States

Related Subject Headings

  • Transplant Recipients
  • Surgery
  • Male
  • Macaca mulatta
  • Kidney Transplantation
  • Immunosuppressive Agents
  • Graft Survival
  • Graft Rejection
  • Drug Therapy, Combination
  • CD40 Antigens