Technical challenges and clinical relevance of single antigen bead C1q/C3d testing and IgG subclass analysis of human leukocyte antigen antibodies

Karahan, Gonca E.; Claas, Frans H.J.; Heidt, Sebastiaan

doi:10.1111/tri.13327

Cited by 14 publications

(16 citation statements)

References 87 publications

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“…In addition, SAB MFI should not be used as a quantitative assay since it has a relatively high coefficient of variation ( 51 ). Thus, current technology cannot determine antibody titers or the clinical and biological relevance of positive test results ( 51 , 54 ). In addition, although pretransplant DSA and dn HLA antibody development are strongly associated with AMR and graft failure ( 43 , 55 – 60 ), no studies show that interventions affecting DSA levels or specificities after transplantation predict long-term improvement in graft survival rates ( Table 2 ) ( 54 , 61 – 63 ).…”

Section: Single Markers As Surrogate Endpointmentioning

confidence: 99%

Surrogate Endpoints for Late Kidney Transplantation Failure

Naesens¹,

Budde

Hilbrands³

et al. 2022

Transpl Int

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In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.

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Section: Single Markers As Surrogate Endpointmentioning

confidence: 99%

Surrogate Endpoints for Late Kidney Transplantation Failure

Naesens¹,

Budde

Hilbrands³

et al. 2022

Transpl Int

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“…Sera are incubated together with recombinant C1q. An antibody capable to bind C1q is detected by a phycoerythrin (PE)-conjugated anti-C1q antibody (Figure 2) [38]. As IgM or IgG cannot be identified by this anti-C1q antibody, C1q binding anti-HLA antibodies detected can be either IgM or IgG isotype.…”

Section: Principles Of C1q C3d and C4d Binding Assaysmentioning

confidence: 99%

Novel Diagnostic and Therapeutic Approach to Antibody-Mediated Rejections in Heart Transplantation

Watanabe¹,

Fukushima²

2020

Immunosuppression

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Despite the improvement of immunosuppressive therapy in heart transplantation (HTx), antibody-mediated rejection (AMR) is still a great obstacle to prolong cardiac graft survival. Anti-donor-specific antibodies (DSAs), especially anti-donor human leukocyte antigen (HLA) antibody, lead to heart graft failure resulting in hemodynamic consequence and often in the recipient death. To prevent hyperacute rejection, prospective complement-dependent cytotoxicity test has been performed in every cardiac donor in Japan. But in other solid organ transplantations, flow cytometry crossmatch has been recently recommended to crossmatch to select the recipient in Japan as well as the world. However, flow cytometry is too sensitive to select the recipient, because not all DSAs determined by flow cytometry are cytotoxic to the cardiac graft. On the first complement classical pathway, alloantibodies bind to HLA antigens on cells of the graft and then recruit C1q, which is essential to make membrane attack complex and kill the cell. We review a role of the novel monitoring method of complement pathway regarding C1q in occurrence of AMR and its diagnostic and therapeutic significance in managing AMR in HTx.

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“…17,18 Given that IgG subclass analysis may elucidate a relationship between DSA and liver allograft injury, we aimed to explore and solidify both the assay itself and analytical strategies to optimize clinical utility. However, current reagents for subclass determination vary in sensitivity and specificity, and thresholds used to determine IgG subclass positivity have been arbitrarily set based on experience with pan-IgG detection antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…However, current reagents for subclass determination vary in sensitivity and specificity, and thresholds used to determine IgG subclass positivity have been arbitrarily set based on experience with pan-IgG detection antibodies. 17,18 Given that IgG subclass analysis may elucidate a relationship between DSA and liver allograft injury, we aimed to explore and solidify both the assay itself and analytical strategies to optimize clinical utility.…”

Section: Introductionmentioning

confidence: 99%

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

Jackson

Kanaparthi

Burrell

et al. 2020

American Journal of Transplantation

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The impact of donor-specific HLA antibody (DSA) following liver transplantation remains controversial. We hypothesized DSA IgG subclass characteristics, compared to total DSA IgG, might correlate with specific histopathological phenotype(s) of subclinical graft injury. We therefore studied 129 stable, arguably "clinically ideal," pediatric liver recipients at the time of a screening biopsy to enter an immunosuppression withdrawal trial. Sixty-five (50%) subjects tested positive for class II DSA.IgG subclass profile was characterized by mean fluorescence intensity (MFI) and normalized subclass composition (>5%). A prominent IgG4 DSA profile was strongly correlated with greater HLA mismatch, a histopathological phenotype characterized by the presence of interface activity (with variable degrees of fibrosis), and a transcriptional profile of attenuated T cell-mediated rejection. Specifically, compared to those without class II DSA, those with IgG4 class II DSA MFI sum >2000 exhibited an odds ratio (OR) of 20.79 (95% confidence interval [CI] 4.38-98.69) and IgG4 subclass composition >5% exhibited an OR of 8.99 (95% CI 2.70-29.9). Our data suggest that IgG4 DSA may serve as a useful biomarker to identify, among clinically and biochemically stable liver transplant recipients, a subset with histological and transcriptional features indicative of an active, suboptimally controlled alloimmune response. K E Y W O R D S alloantibody, clinical research/practice, histocompatibility, immunosuppressive regimensminimization/withdrawal, liver transplantation/hepatology, pediatrics, rejection: subclinical S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Jackson AM, Kanaparthi S, Burrell BE, et al. IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients. Am

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Technical challenges and clinical relevance of single antigen bead C1q/C3d testing and IgG subclass analysis of human leukocyte antigen antibodies

Cited by 14 publications

References 87 publications

Surrogate Endpoints for Late Kidney Transplantation Failure

Surrogate Endpoints for Late Kidney Transplantation Failure

Novel Diagnostic and Therapeutic Approach to Antibody-Mediated Rejections in Heart Transplantation

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

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