Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients

William Robert Morrow, Elizabeth A. Frazier, William T. Mahle, Terry O. Harville, Sherry E. Pye, Kenneth R. Knecht, Emily L. Howard, R. Neal Smith, Robert L. Saylors, Xiomara Garcia, Robert D.B. Jaquiss, E. Steve Woodle

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

BACKGROUND.: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS.: Patients received four intravenous dose of bortezomib (1.3 mg/m) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS.: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS.: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

Original languageEnglish (US)
Pages (from-to)319-324
Number of pages6
JournalTransplantation
Volume93
Issue number3
DOIs
StatePublished - Feb 15 2012

Fingerprint

HLA Antigens
Tissue Donors
Pediatrics
Transplants
Antibodies
Plasmapheresis
Intravenous Immunoglobulins
Plasma Cells
Bortezomib
Biopsy
Antibody-Producing Cells
Proteasome Inhibitors
Retreatment
Antibody Specificity
Therapeutics
Immunoglobulin G
Fluorescence
Hemodynamics

Keywords

  • Antibody-mediated rejection
  • Donor-specific antibodies
  • Pediatric heart transplant

ASJC Scopus subject areas

  • Transplantation

Cite this

Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients. / Morrow, William Robert; Frazier, Elizabeth A.; Mahle, William T.; Harville, Terry O.; Pye, Sherry E.; Knecht, Kenneth R.; Howard, Emily L.; Neal Smith, R.; Saylors, Robert L.; Garcia, Xiomara; Jaquiss, Robert D.B.; Woodle, E. Steve.

In: Transplantation, Vol. 93, No. 3, 15.02.2012, p. 319-324.

Research output: Contribution to journalArticle

Morrow, WR, Frazier, EA, Mahle, WT, Harville, TO, Pye, SE, Knecht, KR, Howard, EL, Neal Smith, R, Saylors, RL, Garcia, X, Jaquiss, RDB & Woodle, ES 2012, 'Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients', Transplantation, vol. 93, no. 3, pp. 319-324. https://doi.org/10.1097/TP.0b013e31823f7eea
Morrow, William Robert ; Frazier, Elizabeth A. ; Mahle, William T. ; Harville, Terry O. ; Pye, Sherry E. ; Knecht, Kenneth R. ; Howard, Emily L. ; Neal Smith, R. ; Saylors, Robert L. ; Garcia, Xiomara ; Jaquiss, Robert D.B. ; Woodle, E. Steve. / Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients. In: Transplantation. 2012 ; Vol. 93, No. 3. pp. 319-324.
@article{591ce226faa44f28af41e1ef675c517e,
title = "Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients",
abstract = "BACKGROUND.: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS.: Patients received four intravenous dose of bortezomib (1.3 mg/m) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS.: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS.: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.",
keywords = "Antibody-mediated rejection, Donor-specific antibodies, Pediatric heart transplant",
author = "Morrow, {William Robert} and Frazier, {Elizabeth A.} and Mahle, {William T.} and Harville, {Terry O.} and Pye, {Sherry E.} and Knecht, {Kenneth R.} and Howard, {Emily L.} and {Neal Smith}, R. and Saylors, {Robert L.} and Xiomara Garcia and Jaquiss, {Robert D.B.} and Woodle, {E. Steve}",
year = "2012",
month = "2",
day = "15",
doi = "10.1097/TP.0b013e31823f7eea",
language = "English (US)",
volume = "93",
pages = "319--324",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients

AU - Morrow, William Robert

AU - Frazier, Elizabeth A.

AU - Mahle, William T.

AU - Harville, Terry O.

AU - Pye, Sherry E.

AU - Knecht, Kenneth R.

AU - Howard, Emily L.

AU - Neal Smith, R.

AU - Saylors, Robert L.

AU - Garcia, Xiomara

AU - Jaquiss, Robert D.B.

AU - Woodle, E. Steve

PY - 2012/2/15

Y1 - 2012/2/15

N2 - BACKGROUND.: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS.: Patients received four intravenous dose of bortezomib (1.3 mg/m) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS.: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS.: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

AB - BACKGROUND.: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS.: Patients received four intravenous dose of bortezomib (1.3 mg/m) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS.: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS.: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

KW - Antibody-mediated rejection

KW - Donor-specific antibodies

KW - Pediatric heart transplant

UR - http://www.scopus.com/inward/record.url?scp=84856439102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856439102&partnerID=8YFLogxK

U2 - 10.1097/TP.0b013e31823f7eea

DO - 10.1097/TP.0b013e31823f7eea

M3 - Article

VL - 93

SP - 319

EP - 324

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 3

ER -