Humoral Compensation After Bortezomib Treatment of Allosensitized Recipients

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2017 Feb 25

PMID 28232617

Citations 36

Authors

Jean Kwun

Christopher Burghuber

Miriam Manook

Neal Iwakoshi

Adriana Gibby

Jung Joo Hong

Stuart Knechtle

Affiliations

Soon will be listed here.

Abstract

The efficacy of bortezomib monotherapy in desensitizing kidney transplant candidates with preformed donor-specific antibodies remains unclear. We evaluated the effect of bortezomib on preformed antibodies and upstream components of the B cell response in a primate model sensitized by fully mismatched allogeneic skin transplants to provide mechanistic insights regarding the use of bortezomib as a means of desensitization. Bortezomib treatment given intravenously twice weekly for 1 month (1.3 mg/m per dose) clearly reduced the numbers of antibody-producing cells and CD38CD19CD20 plasma cells in the bone marrow (<0.05), but donor-specific alloantibody levels did not decrease. We observed a rapid but transient induction of circulating IgG B cells and an increased number of proliferating B cells in the lymph nodes after 1 month of treatment. Notably, bortezomib treatment induced germinal center B cell and follicular helper T cell expansion in the lymph nodes. These data suggest that bortezomib-induced plasma cell depletion triggers humoral compensation.

Citing Articles

Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection.

Dragon A, Bonifacius A, Lienenklaus S, Verboom M, Gerhards J, Ius F Mol Ther. 2025; 33(3):1031-1047.

PMID: 39799394 PMC: 11897811. DOI: 10.1016/j.ymthe.2025.01.009.

CD154 blockade effectively controls antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients.

Anwar I, DeLaura I, Ladowski J, Schiliro D, Gao Q, Manook M Sci Transl Med. 2025; 17(779):eadn8130.

PMID: 39742504 PMC: 11797747. DOI: 10.1126/scitranslmed.adn8130.

Contribution of long-lived plasma cells to antibody-mediated allograft rejection.

Jang E, Youn J Clin Transplant Res. 2024; 38(4):341-353.

PMID: 39690904 PMC: 11732765. DOI: 10.4285/ctr.24.0047.

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model.

Schmitz R, Manook M, Fitch Z, Anwar I, DeLaura I, Olaso D Front Transplant. 2024; 2:1230393.

PMID: 38993898 PMC: 11235304. DOI: 10.3389/frtra.2023.1230393.

Translation of therapeutic strategies to modulate B cell reponses from non-human primate models to human kidney transplantation.

Knechtle S, Kwun J, Song S, Jackson A, Williams K, Sanoff S Front Transplant. 2024; 2:1176796.

PMID: 38993890 PMC: 11235383. DOI: 10.3389/frtra.2023.1176796.

References

Goenka R, Scholz J, Sindhava V, Cancro M . New roles for the BLyS/BAFF family in antigen-experienced B cell niches. Cytokine Growth Factor Rev. 2014; 25(2):107-13. PMC: 3999179. DOI: 10.1016/j.cytogfr.2014.01.001. View

Mulder A, Heidt S, Vergunst M, Roelen D, Claas F . Proteasome inhibition profoundly affects activated human B cells. Transplantation. 2013; 95(11):1331-7. DOI: 10.1097/TP.0b013e3182911739. View

Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen J, Mooney N . Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013; 369(13):1215-26. DOI: 10.1056/NEJMoa1302506. View

Mezo A, McDonnell K, Tan Hehir C, Low S, Palombella V, Stattel J . Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci U S A. 2008; 105(7):2337-42. PMC: 2268137. DOI: 10.1073/pnas.0708960105. View

Morrow W, Frazier E, Mahle W, Harville T, Pye S, Knecht K . Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients. Transplantation. 2011; 93(3):319-24. PMC: 3730122. DOI: 10.1097/TP.0b013e31823f7eea. View

Jordan S, Tyan D, Stablein D, McIntosh M, Rose S, Vo A . Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004; 15(12):3256-62. DOI: 10.1097/01.ASN.0000145878.92906.9F. View

Sberro-Soussan R, Zuber J, Suberbielle-Boissel C, Candon S, Martinez F, Snanoudj R . Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies. Am J Transplant. 2010; 10(3):681-6. DOI: 10.1111/j.1600-6143.2009.02968.x. View

Kim E, Kwun J, Gibby A, Hong J, Farris 3rd A, Iwakoshi N . Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2013; 14(1):59-69. PMC: 3985346. DOI: 10.1111/ajt.12526. View

Perry D, Burns J, Pollinger H, Amiot B, Gloor J, Gores G . Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2008; 9(1):201-9. DOI: 10.1111/j.1600-6143.2008.02461.x. View

10.

Kortuem K, Stewart A . Carfilzomib. Blood. 2013; 121(6):893-7. DOI: 10.1182/blood-2012-10-459883. View

11.

Guthoff M, Schmid-Horch B, Weisel K, Haring H, Konigsrainer A, Heyne N . Proteasome inhibition by bortezomib: effect on HLA-antibody levels and specificity in sensitized patients awaiting renal allograft transplantation. Transpl Immunol. 2012; 26(4):171-5. DOI: 10.1016/j.trim.2012.01.002. View

12.

Jackson A, Kraus E, Orandi B, Segev D, Montgomery R, Zachary A . A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation. Kidney Int. 2014; 87(2):409-16. PMC: 4305036. DOI: 10.1038/ki.2014.261. View

13.

Bentall A, Cornell L, Gloor J, Park W, Gandhi M, Winters J . Five-year outcomes in living donor kidney transplants with a positive crossmatch. Am J Transplant. 2012; 13(1):76-85. DOI: 10.1111/j.1600-6143.2012.04291.x. View

14.

Snyder L, Gray A, Reynolds J, Arepally G, Bedoya A, Hartwig M . Antibody desensitization therapy in highly sensitized lung transplant candidates. Am J Transplant. 2014; 14(4):849-56. PMC: 4336170. DOI: 10.1111/ajt.12636. View

15.

Moreno Gonzales M, Gandhi M, Schinstock C, Moore N, Smith B, Braaten N . 32 Doses of Bortezomib for Desensitization Is Not Well Tolerated and Is Associated With Only Modest Reductions in Anti-HLA Antibody. Transplantation. 2016; 101(6):1222-1227. PMC: 4935916. DOI: 10.1097/TP.0000000000001330. View

16.

Burghuber C, Kwun J, Page E, Manook M, Gibby A, Leopardi F . Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology. Am J Transplant. 2015; 16(6):1726-38. PMC: 4874845. DOI: 10.1111/ajt.13688. View

17.

Pelletier N, McHeyzer-Williams L, Wong K, Urich E, Fazilleau N, McHeyzer-Williams M . Plasma cells negatively regulate the follicular helper T cell program. Nat Immunol. 2010; 11(12):1110-8. PMC: 3058870. DOI: 10.1038/ni.1954. View

18.

Woodle E, Shields A, Ejaz N, Sadaka B, Girnita A, Walsh R . Prospective iterative trial of proteasome inhibitor-based desensitization. Am J Transplant. 2014; 15(1):101-18. DOI: 10.1111/ajt.13050. View

19.

Schmidt N, Alloway R, Walsh R, Sadaka B, Shields A, Girnita A . Prospective evaluation of the toxicity profile of proteasome inhibitor-based therapy in renal transplant candidates and recipients. Transplantation. 2012; 94(4):352-61. DOI: 10.1097/TP.0b013e318257acf6. View

20.

Patel J, Everly M, Chang D, Kittleson M, Reed E, Kobashigawa J . Reduction of alloantibodies via proteasome inhibition in cardiac transplantation. J Heart Lung Transplant. 2011; 30(12):1320-6. DOI: 10.1016/j.healun.2011.08.009. View