DSA-FXM: Accelerated Donor-specific Flow Crossmatch Discriminating Class I and II Antibody Specifically and Only to Donor HLA for Determining True Incompatibility.

Background: Worldwide, a final crossmatch is the gold standard for determining compatibility between patient and donor before solid organ transplantation and preventing hyperacute rejection. In the absence of autoantibodies, an incompatible crossmatch in a sensitized patient is attributed to mismatched donor HLA. However, current physical crossmatch methods cannot distinguish reactivity to HLA from other clinically irrelevant cell surface targets nor the class of HLA if it is the target.

Mapping and definition of HLA class I and II serologic epitopes using an unbiased reverse engineering strategy.

Current models describing HLA epitopes are both theoretical and empirical. Each has limitations yielding discordant results and increasingly complex modeling. The models make a priori assumptions that epitopes must be present only on the mature protein, solvent accessible, on the 'top' (peptide binding surface) of the molecule, restricted to the same class as the antibody, and in the same position on the target allele if reactive to more than one locus.

A reverse-engineering strategy utilizing the integration of single antigen beads and NGS HLA genotypes to detect potential antibody inducing epitopes.

Central to the idea of antibody recognition is some degree of foreignness of the target antigen compared to the antibody producer. Epitopes are distinct regions on an antigen to which antibody can be elicited and bound. However, for HLA antigens, there is no consensus definition of what represents the minimal functional immunogenic unit of dissimilarity.

Sensitization in Heart Transplantation: Emerging Knowledge: A Scientific Statement From the American Heart Association.

Sensitization, defined as the presence of circulating antibodies, presents challenges for heart transplant recipients and physicians. When present, sensitization can limit a transplantation candidate's access to organs, prolong wait time, and, in some cases, exclude the candidate from heart transplantation altogether. The management of sensitization is not yet standardized, and current therapies have not yielded consistent results.

Correction: Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis.

[This corrects the article DOI: 10.1371/journal.pmed.

Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis.

Background: Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations.

Methods And Findings: To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018.

Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA.

Application, technical issues, and interpretation of C1q for graft outcome.

Purpose Of Review: Significant interest and controversy surround the use of C1q for determining risk of antibody-mediated rejection (AMR) and graft loss. Alternate models for predicting outcomes have been proposed. This review focuses on the correlation of currently utilized assays for outcome, together with the technical and theoretical limitations, to distill current thinking.

Immunological Effect of Skin Allograft in Burn Treatment: Impact on Future Vascularized Composite Allotransplantation.

Skin allografts are the gold standard in temporary burn wound coverage, but allografts are hypothesized to place a high antigenic load on recipients. This project aims to determine the degree of human leukocyte antigen sensitization in burn patients treated with allografts. Serum was obtained from nine adult, nontransfused, and nontransplanted burn patients treated with allografts.

HLA desensitization with bortezomib in a highly sensitized pediatric patient.

The proteasome inhibitor bortezomib has been used with variable success in the treatment of AMR following heart transplant. There is limited experience with this agent as a pretransplant desensitizing therapy. We report a case of successful HLA desensitization with a bortezomib-based protocol prior to successful heart transplantation.

Antibody-mediated rejection despite inhibition of terminal complement.

Terminal complement blockade has been shown to decrease the incidence of early acute antibody-mediated rejection (eAMR) in the first month after positive cross-match kidney transplant recipients, yet some patients still develop eAMR. The current study investigated possible mechanisms of eAMR despite eculizumab treatment. Of the 26 patients treated with eculizumab, two developed clinical eAMR and another patient developed histologic signs of eAMR without graft dysfunction ('subclinical eAMR').

Sensitization from transfusion in patients awaiting primary kidney transplant.

Background: Sensitization to human leukocyte antigen (HLA) from red blood cell (RBC) transfusion is poorly quantified and is based on outdated, insensitive methods. The objective was to evaluate the effect of transfusion on the breadth, magnitude and specificity of HLA antibody formation using sensitive and specific methods.

Methods: Transfusion, demographic and clinical data from the US Renal Data System were obtained for patients on dialysis awaiting primary kidney transplant who had ≥ 2 HLA antibody measurements using the Luminex single-antigen bead assay.

C1q assay for the detection of complement fixing antibody to HLA antigens.

Solid phase Luminex(®) and flow cytometric single antigen bead assays offer exquisite sensitivity and specificity for HLA antibody detection. Unlike the historical complement-dependent cytotoxicity (CDC) method, these assays do not distinguish complement fixing from non-complement fixing antibody, the former of which are considered the most clinically relevant in the peri-transplant period. This chapter describes a novel solid phase C1q binding assay to distinguish HLA antibodies that can bind the first component of complement (C1q).

Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.

Background: The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients.

New approaches for detecting complement-fixing antibodies.

Purpose Of Review: Complement-fixing human leukocyte antigen (HLA) antibodies are a contraindication to solid organ transplant. Newer solid phase assays for HLA antibody definition have created treatment quandaries because many more antibodies are detected by these methods. It is unclear which of the antibodies identified are clinically relevant as all IgG-binding antibodies are detected whether they can fix complement or not.

Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss.

Long-term outcomes following renal transplantation remain disappointing. Recently, interest has focused on the antibody-mediated component of allograft injury and the deleterious effects of DSA. We applied a novel C1q solid-phase assay in parallel with the standard IgG SAB assay to identify DSA with the potential to activate complement by binding C1q.

Complement (C1q) fixing solid-phase screening for HLA antibodies increases the availability of compatible platelet components for refractory patients.

Background: Immune refractoriness to platelet (PLT) transfusion is primarily due to HLA antibody. Patients at our institution are identified as refractory due to HLA by a Luminex-based immunoglobulin (Ig)G-single-antigen-bead (SAB) assay, but in highly sensitized patients, antigen-negative compatible donors cannot be found due to the high sensitivity of the IgG-SAB method. We developed an assay that detects only HLA antibodies binding the first complement component (C1q).

C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation.

Background: Human leukocyte antigen (HLA) antibodies, especially those that fix complement, are associated with antibody-mediated rejection and graft failure. The C1q assay on single antigen beads detects a subset of HLA antibodies that can fix complement and precede C4d deposition. The aim of this study was to determine whether C1q-fixing antibodies distinguish de novo donor-specific antibodies (DSA) that are clinically relevant and harmful.

Consensus opinion from the antibody working group on the diagnosis, reporting, and risk assessment for antibody-mediated rejection and desensitization protocols.

During the past few decades, much of the experimental and clinical effort in solid-organ transplantation has been directed toward ameliorating or abrogating T-cell-mediated responses. As a result, universally understood and accepted nomenclature and diagnostic criteria have evolved. Humoral immunity in transplantation has yet to undergo a similar renaissance.

The report of a national conference on the wait list for kidney transplantation.

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys.