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Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients.

Publication ,  Journal Article
Ezekian, B; Schroder, PM; Mulvihill, MS; Barbas, A; Collins, B; Freischlag, K; Yoon, J; Yi, JS; Smith, F; Olaso, D; Saccoccio, FM; Permar, S ...
Published in: J Am Soc Nephrol
December 2019

BACKGROUND: Patients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact. METHODS: To investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation. RESULTS: The group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection. CONCLUSIONS: Desensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

December 2019

Volume

30

Issue

12

Start / End Page

2399 / 2411

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • T-Lymphocytes, Helper-Inducer
  • Skin Transplantation
  • Proteasome Inhibitors
  • Preoperative Care
  • Plasma Cells
  • Oligopeptides
  • Male
  • Macaca mulatta
  • Lymphocyte Activation
 

Citation

APA
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ICMJE
MLA
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Ezekian, B., Schroder, P. M., Mulvihill, M. S., Barbas, A., Collins, B., Freischlag, K., … Knechtle, S. J. (2019). Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients. J Am Soc Nephrol, 30(12), 2399–2411. https://doi.org/10.1681/ASN.2019030304
Ezekian, Brian, Paul M. Schroder, Michael S. Mulvihill, Andrew Barbas, Bradley Collins, Kyle Freischlag, Janghoon Yoon, et al. “Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients.J Am Soc Nephrol 30, no. 12 (December 2019): 2399–2411. https://doi.org/10.1681/ASN.2019030304.
Ezekian B, Schroder PM, Mulvihill MS, Barbas A, Collins B, Freischlag K, Yoon J, Yi JS, Smith F, Olaso D, Saccoccio FM, Permar S, Farris AB, Kwun J, Knechtle SJ. Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients. J Am Soc Nephrol. 2019 Dec;30(12):2399–2411.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

December 2019

Volume

30

Issue

12

Start / End Page

2399 / 2411

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • T-Lymphocytes, Helper-Inducer
  • Skin Transplantation
  • Proteasome Inhibitors
  • Preoperative Care
  • Plasma Cells
  • Oligopeptides
  • Male
  • Macaca mulatta
  • Lymphocyte Activation