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Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.

Publication ,  Journal Article
Schroder, PM; Schmitz, R; Fitch, ZW; Ezekian, B; Yoon, J; Choi, AY; Manook, M; Barbas, A; Leopardi, F; Song, M; Farris, AB; Collins, B ...
Published in: Kidney Int
January 2021

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m2 IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27-CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.

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Published In

Kidney Int

DOI

EISSN

1523-1755

Publication Date

January 2021

Volume

99

Issue

1

Start / End Page

161 / 172

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Primates
  • Oligopeptides
  • Immunosuppressive Agents
  • Humans
  • Graft Survival
  • Graft Rejection
  • Desensitization, Immunologic
  • Animals
  • Abatacept
 

Citation

APA
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ICMJE
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Schroder, P. M., Schmitz, R., Fitch, Z. W., Ezekian, B., Yoon, J., Choi, A. Y., … Knechtle, S. J. (2021). Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Kidney Int, 99(1), 161–172. https://doi.org/10.1016/j.kint.2020.08.020
Schroder, Paul M., Robin Schmitz, Zachary W. Fitch, Brian Ezekian, Janghoon Yoon, Ashley Y. Choi, Miriam Manook, et al. “Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.Kidney Int 99, no. 1 (January 2021): 161–72. https://doi.org/10.1016/j.kint.2020.08.020.
Schroder PM, Schmitz R, Fitch ZW, Ezekian B, Yoon J, Choi AY, et al. Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Kidney Int. 2021 Jan;99(1):161–72.
Schroder, Paul M., et al. “Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.Kidney Int, vol. 99, no. 1, Jan. 2021, pp. 161–72. Pubmed, doi:10.1016/j.kint.2020.08.020.
Schroder PM, Schmitz R, Fitch ZW, Ezekian B, Yoon J, Choi AY, Manook M, Barbas A, Leopardi F, Song M, Farris AB, Collins B, Kwun J, Knechtle SJ. Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Kidney Int. 2021 Jan;99(1):161–172.
Journal cover image

Published In

Kidney Int

DOI

EISSN

1523-1755

Publication Date

January 2021

Volume

99

Issue

1

Start / End Page

161 / 172

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Primates
  • Oligopeptides
  • Immunosuppressive Agents
  • Humans
  • Graft Survival
  • Graft Rejection
  • Desensitization, Immunologic
  • Animals
  • Abatacept