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

Autor:	Ezekian B; Department of Surgery, Duke Transplant Center., Schroder PM; Department of Surgery, Duke Transplant Center., Mulvihill MS; Department of Surgery, Duke Transplant Center., Barbas A; Department of Surgery, Duke Transplant Center., Collins B; Department of Surgery, Duke Transplant Center., Freischlag K; Department of Surgery, Duke Transplant Center., Yoon J; Department of Surgery, Duke Transplant Center., Yi JS; Division of Surgical Sciences, Department of Surgery, Duke University, Durham, North Carolina; and., Smith F; Division of Laboratory Animal Resources, and., Olaso D; Department of Surgery, Duke Transplant Center., Saccoccio FM; Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina., Permar S; Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina., Farris AB; Department of Pathology, Emory School of Medicine, Atlanta, Georgia., Kwun J; Department of Surgery, Duke Transplant Center, jean.kwun@duke.edu stuart.knechtle@duke.edu., Knechtle SJ; Department of Surgery, Duke Transplant Center, jean.kwun@duke.edu stuart.knechtle@duke.edu.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2019 Dec; Vol. 30 (12), pp. 2399-2411. Date of Electronic Publication: 2019 Oct 28.
DOI:	10.1681/ASN.2019030304
Abstrakt:	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. (Copyright © 2019 by the American Society of Nephrology.)
Databáze:	MEDLINE
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