BACKGROUND: Donor specific alloantibody producing plasma cells (DSA-PCs) appear resistant to conventional immunosuppressive agents. This study aimed to determine the impact of pretransplant monotherapy with the proteasome inhibitor bortezomib on DSA-PCs in sensitized renal allograft candidates and to assess if DSA-PC depletion would enhance the efficacy of DSA removal using plasma exchange (PE). METHODS: Only patients with DSA levels considered too high to successfully undergo transplantation with PE alone were included in this study: i.e. those with a baseline B flow cytometric crossmatch (BFXM) >450 against a potential living donor.Four sensitized patients received 4 doses (1.3 mg/m/dose) of bortezomib and 4 received 16 doses. The number of DSA-PCs was determined pre and post-treatment using an ELISPOT assay. Five of these patients underwent post-treatment PE and their response was compared to 8 highly-sensitized patients (BFXM >450) who underwent PE alone. RESULTS: When considering all 8 patients as one group, bortezomib treatment decreased DSA-PCs in the marrow (mean±SD=16.7±14.5 DSA-PCs/ml pre-treatment vs. 6.2±3.6 DSA-PCs/ml after treatment, P=0.048). In the time frame of the study, bortezomib alone did not decrease serum DSA levels. However, five bortezomib treated patients underwent PE and showed a greater decease in DSA compared to the historical control group of 8 sensitized patients who underwent PE alone (mean decrease in BFXM channel shift=272.6±92.1 with bortezomib vs 95.4±72.2 in PE alone P=0.008). CONCLUSIONS: Bortezomib depletes DSA-PCs and appears to potentiate DSA removal by PE in sensitized renal transplant recipients.
BACKGROUND:Donor specific alloantibody producing plasma cells (DSA-PCs) appear resistant to conventional immunosuppressive agents. This study aimed to determine the impact of pretransplant monotherapy with the proteasome inhibitor bortezomib on DSA-PCs in sensitized renal allograft candidates and to assess if DSA-PC depletion would enhance the efficacy of DSA removal using plasma exchange (PE). METHODS: Only patients with DSA levels considered too high to successfully undergo transplantation with PE alone were included in this study: i.e. those with a baseline B flow cytometric crossmatch (BFXM) >450 against a potential living donor.Four sensitized patients received 4 doses (1.3 mg/m/dose) of bortezomib and 4 received 16 doses. The number of DSA-PCs was determined pre and post-treatment using an ELISPOT assay. Five of these patients underwent post-treatment PE and their response was compared to 8 highly-sensitized patients (BFXM >450) who underwent PE alone. RESULTS: When considering all 8 patients as one group, bortezomib treatment decreased DSA-PCs in the marrow (mean±SD=16.7±14.5 DSA-PCs/ml pre-treatment vs. 6.2±3.6 DSA-PCs/ml after treatment, P=0.048). In the time frame of the study, bortezomib alone did not decrease serum DSA levels. However, five bortezomib treated patients underwent PE and showed a greater decease in DSA compared to the historical control group of 8 sensitized patients who underwent PE alone (mean decrease in BFXM channel shift=272.6±92.1 with bortezomib vs 95.4±72.2 in PE alone P=0.008). CONCLUSIONS:Bortezomib depletes DSA-PCs and appears to potentiate DSA removal by PE in sensitized renal transplant recipients.
Authors: Hidetaka Hara; Andrew Bentall; Cassandra Long; Jason Fang; Oleg Andreyev; John Lunz; Mohamed Ezzelarab; Kareem M Abu-Elmagd; Ron Shapiro; David Ayares; Mark Stegall; David K C Cooper Journal: Xenotransplantation Date: 2013-09-03 Impact factor: 3.907
Authors: E Steve Woodle; Simon Tremblay; Paul Brailey; Alin Girnita; Rita R Alloway; Bruce Aronow; Nupur Dasgupta; Frederic Ebstein; Peter-Michael Kloetzel; Min Jae Lee; Kyung B Kim; Harinder Singh; James J Driscoll Journal: Am J Transplant Date: 2019-12-11 Impact factor: 8.086
Authors: Farsad Eskandary; Heinz Regele; Lukas Baumann; Gregor Bond; Nicolas Kozakowski; Markus Wahrmann; Luis G Hidalgo; Helmuth Haslacher; Christopher C Kaltenecker; Marie-Bernadette Aretin; Rainer Oberbauer; Martin Posch; Anton Staudenherz; Ammon Handisurya; Jeff Reeve; Philip F Halloran; Georg A Böhmig Journal: J Am Soc Nephrol Date: 2017-12-14 Impact factor: 10.121
Authors: Manuel A Moreno Gonzales; Manish J Gandhi; Carrie A Schinstock; Natalie A Moore; Byron H Smith; Nong Y Braaten; Mark D Stegall Journal: Transplantation Date: 2017-06 Impact factor: 4.939
Authors: Christopher K Burghuber; Miriam Manook; Brian Ezekian; Adriana C Gibby; Frank V Leopardi; Minqing Song; Jennifer Jenks; Frances Saccoccio; Sallie Permar; Alton B Farris; Neal N Iwakoshi; Jean Kwun; Stuart J Knechtle Journal: Am J Transplant Date: 2018-09-17 Impact factor: 8.086
Authors: Nick Willcox; Pilar Martinez-Martinez; Mario Losen; Alejandro M Gomez; Kathleen Vrolix; Jonas Hummel; Gisela Nogales-Gadea; Abhishek Saxena; Hans Duimel; Fons Verheyen; Peter C Molenaar; Wim A Buurman; Marc H De Baets Journal: J Immunol Date: 2014-06-27 Impact factor: 5.422