Reduction of alloantibodies via proteosome inhibition in cardiac transplantation

The presence of donor-specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen-antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)-treated samples, as well as titration studies and peak MFI values of over 7000 Luminex-based single-antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen-antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength.Abbreviations: AMR, antibody-mediated rejection; DSA, donor-specific antibody; EDTA, ethylenediaminetetraacetic acid; MFI, mean fluorescence intensity; SAB, single antigen beads; SPA, solid phase assays

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“…Given the breadth and depth of sensitization, the decision was to use bortezomib-based desensitization (10,11). …”

Section: Resultsmentioning

confidence: 99%

Assessing Antibody Strength: Comparison of MFI, C1q, and Titer Information

Tambur

Herrera

Haarberg

et al. 2015

American Journal of Transplantation

225

217

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“…However, the major advantage of PI has been in overcoming humoral barriers. 78,79 Eckman and associates demonstrated that a bortezomib-based regimen provided effective therapy for late, refractory AMR in a heart transplant adult recipient, and it was well tolerated. This remarkably positive experience, despite the refractory nature of the AMR episode, argues strongly for continuing to evaluate bortezomib use in these patients.…”

Section: Novel Approaches On Sensitized Patientsmentioning

confidence: 99%

Current Concepts in Histocompatibility During Heart Transplant

Picascia

Grimaldi²,

Zullo³

et al. 2012

Exp Clin Transplant

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Sensitized candidates for heart transplant usually end up on a long waiting list and have an increased risk of rejection, graft loss, and incidence of cardiac allograft vasculopathy. An increasing number of studies have demonstrated the negative effect of preformed and posttransplant antibodies on graft survival. Thus, in sensitized patients, the combination of new, appropriate, desensitization protocols, and monitoring of posttransplant development of donor-specific antibodies may improve short-term and long-term outcomes. Introduction of more-sensitive and more-specific techniques for antibody detection provides a valid tool for assessing the degree of pretransplant HLA histocompatibility, and, therefore, predicting the results of crossmatch in sensitized patients, which are difficult to transplant. Currently, there are no accurate and standard methods to determine the functional characteristics of antibodies detected by solid-phase assay and, therefore, to predict their clinical relevance. Therefore, the future of heart transplantation requires a better understanding of tissue typing techniques and the effect of anti-HLA antibodies on clinical outcome to prevent discrimination against sensitized patients at the time of organ allocation.

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“…In heart transplantation, bortezomib in combination with plasmapheresis was studied in seven sensitized patients awaiting heart transplantation who, despite prior treatment with rituximab, IVIG, and/or plasmapheresis, continued to have high levels of antibodies and cPRA [29]. In this study, bortezomib appeared to be generally well-tolerated, with treatable infection the most common adverse effect.…”

Section: Rituximabmentioning

confidence: 97%

“…A number of desensitization strategies have been shown to be effective, including a combination of plasmapheresis, intravenous immune globulin, and rituximab [28•], and bortezomib [29]. Typically, for these patients, HLA antibody type and strength is determined by single-antigen flow-bead assay prior to initiation of treatment, and repeated two weeks after completion of treatment to assess response.…”

Section: Desensitization Strategiesmentioning

confidence: 99%

Approach to the Sensitized Patient Awaiting Heart Transplantation

Patel¹,

Kobashigawa²

2014

Curr Transpl Rep

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The management of the sensitized patient awaiting heart transplant remains a challenge and an active area of research. The development of solid-phase immunoassays (including the C1q assay) has allowed high-resolution determination of antibodies most likely to be associated with antibody-mediated rejection and adverse outcomes. The precision of these techniques has permitted the adoption of the virtual crossmatch, substantially expanding the donor pool for sensitized patients and reducing wait times to transplant. Desensitization strategies continue to evolve, and the most effective therapies appear to be a combined approach utilizing antibody depletion, targeted B cell or plasma cell therapy, or immunomodulation. Further therapy in addition to cytolytic induction may be required at transplant, with judicious monitoring post-transplant for antibody rebound and rejection.

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Reduction of alloantibodies via proteosome inhibition in cardiac transplantation

Cited by 136 publications

References 25 publications

Assessing Antibody Strength: Comparison of MFI, C1q, and Titer Information

Assessing Antibody Strength: Comparison of MFI, C1q, and Titer Information

Current Concepts in Histocompatibility During Heart Transplant

Approach to the Sensitized Patient Awaiting Heart Transplantation

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