Interpreting Anti-HLA Antibody Testing Data

Schinstock, Carrie A.; Gandhi, Manish J.; Stegall, Mark D.

doi:10.1097/tp.0000000000001203

Cited by 56 publications

(52 citation statements)

References 68 publications

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“…The detection of low-MFI antibodies capable of binding C1q is commonly a consequence of a prozone effect, a phenomenon that hides the real strength of antibodies ( 20 ). The treatment of neat-samples with EDTA or dithiothreitol may somewhat eliminate this inhibitory effect ( 36 ), which would enhance the relationship between the antibody C1q-binding ability and its MFI value. Conversely, high-MFI antibodies incapable of binding C1q could denote low antibody strength, as reported by Tambur et al ( 37 ), who using serum serial dilutions for anti-HLA antibody detection provided a more reliable estimation of their real strength (titer) and demonstrated a strong association between low antibody titers and the inability to bind C1q.…”

Section: Discussionmentioning

confidence: 99%

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome

et al. 2017

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The consolidation of single antigen beads (SAB-panIgG) assay in the detection of preformed anti-human leukocyte antigen (HLA) antibodies has improved transplantation success. However, its high sensitivity has limited the allograft allocation for sensitized patients, increasing their waiting time. A modification of the standard SAB-panIgG assay allows the detection of that subset of antibodies capable of binding C1q (SAB-C1q assay). However, the clinical usefulness of SAB-C1q assay for determining the unacceptable mismatches is under discussion. We retrospectively analyzed the impact of preformed donor-specific anti-HLA antibodies (DSA) according to the C1q-binding ability on allograft outcome, examining 389 single-kidney transplanted patients from deceased donors. Recipients with preformed C1q-binding DSA showed the lowest allograft survival up to 7 years (40.7%) compared to patients with preformed non-C1q-binding DSA (73.4%; p = 0.001) and without DSA (79.1%; p < 0.001). Allograft survival rate was similar between patients with preformed non-C1q-binding DSA and patients without preformed DSA (p = 0.403). Interestingly, among the high-mean fluorescence intensity DSA (≥10,000) population (n = 46), those patients whose DSA were further capable of binding C1q showed a poorer allograft outcome (38.4 vs. 68.9%; p = 0.041). Moreover, in our multivariate predictive model for assessing the risk of allograft loss, the presence of C1q-binding DSA (HR 4.012; CI 95% 2.326–6.919; p < 0.001) but not of non-C1q-binding DSA (HR 1.389; CI 95% 0.784–2.461; p = 0.260) remained an independent predictor after stratifying the DSA population according to the C1q-binding ability and adjusting the model for other pre-transplantation predictive factors including donor age, cold-ischemia time, and HLA-DR mismatches. In conclusion, the unacceptable mismatch definition according to the SAB-C1q assay would improve the risk stratification of allograft loss and increase the limited allograft allocation of highly sensitized patients, shortening their waiting time.

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Section: Discussionmentioning

confidence: 99%

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome

et al. 2017

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“…Thus, Adriana Zeevi emphasized the importance of diluting serum to ensure that the prozone effects are identified. Furthermore, despite the common use of mean fluorescence intensity as an indicator of antibody titer, the SAB assay is not a quantitative measurement and is recognized by the FDA to only indicate presence or absence of DSA . Inclusion of serial dilutions might improve accuracy and allow actual titers to be determined, however costs considerations limit the widespread adoption of this approach.…”

Section: Dsa and Chronic Amrmentioning

confidence: 99%

Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection

Chong

Rothstein

Safa

et al. 2019

American Journal of Transplantation

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Over the past three decades, improved immunosuppression has significantly reduced T cell–mediated acute rejection rates, but long‐term graft survival rates have seen only marginal improvement. The cause of late graft loss has been under intense investigation, and chronic antibody‐mediated rejection (AMR) has been identified as one of the leading causes, thus providing a strong rationale for basic science investigation into donor‐specific B cells and antibodies in transplantation and ways to mitigate their pathogenicity. In 2018, the American Society of Transplantation launched a community‐wide online discussion of Outstanding Questions in Transplantation, and the topic of B cell biology and donor‐specific antibody prevention emerged as a major area of interest to the community, leading to a highly engaged dialogue, with comments from basic and translational scientists as well as physicians (http://community.myast.org/communities/community-home/digestviewer). We have summarized this discussion from a bedside to bench perspective and have organized this review into outstanding questions within the paradigm that AMR is a leading cause of graft loss in the clinic, and points of view that challenge aspects of this paradigm. We also highlight opportunities for basic and translational scientists to contribute to the resolution of these questions, mapping important future directions for the transplant research field.

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“…Subsequently, flow cytometry crossmatch (FCXM) technology was developed with higher sensitivity, and it remains in use for the majority of current kidney transplants. In general, outside of desensitization protocols, the presence of DSA detected by either type of crossmatch would abrogate the transplantation, but various exceptions exist [44]. …”

Section: Pathogenicity Of Hla Antibodiesmentioning

confidence: 99%

“…In our laboratory all patients undergo autocrossmatch, T and B-cell CDCXM, and FCXM in all live donors and any deceased donor when recipient has any past or current sensitization. If SABs used for screening are completely negative in a patient with no sensitizing events, crossmatching may be superfluous [44, 48]. …”

Section: Pathogenicity Of Hla Antibodiesmentioning

confidence: 99%

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

Filippone

Farber

2016

Journal of Immunology Research

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Central to the humoral theory of transplantation is production of antibodies by the recipient against mismatched HLA antigens in the donor organ. Not all mismatches result in antibody production, however, and not all antibodies are pathogenic. Serologic HLA matching has been the standard for solid organ allocation algorithms in current use. Antibodies do not recognize whole HLA molecules but rather polymorphic residues on the surface, called epitopes, which may be shared by multiple serologic HLA antigens. Data are accumulating that epitope analysis may be a better way to determine organ compatibility as well as the potential immunogenicity of given HLA mismatches. Determination of the pathogenicity of alloantibodies is evolving. Potential features include antibody strength (as assessed by antibody titer or, more commonly and inappropriately, mean fluorescence intensity) and ability to fix complement (in vitro by C1q or C3d assay or by IgG subclass analysis). Technical issues with the use of solid phase assays are also of prime importance, such as denaturation of HLA antigens and manufacturing and laboratory variability. Questions and controversies remain, and here we review new relevant data.

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Interpreting Anti-HLA Antibody Testing Data

Cited by 56 publications

References 68 publications

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome

Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

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