RESEARCH IN PROGRESS
Terasaki Innovation Center, Inc. salutes the transplant scientists from around the world who continue to move the legacy of Paul Terasaki forward with their cutting edge research in the role of antibodies
in transplant rejection.
This quarter our featured articles are:
Flow cytometry crossmatching to investigate kidney-biopsy-proven, antibody-mediated rejection in patients who develop de novo donor-specific antibodies.
1. Department of Haematology and Histocompatibility, Amiens University Hospital, Amiens, France; EA Hematim, Jules Verne University of Picardie, Amiens, France.
2. Department of Nephrology and Transplantation, Amiens University Hospital, Amiens, France.
3. Department of Haematology and Histocompatibility, Amiens University Hospital, Amiens, France; EA Hematim, Jules Verne University of Picardie, Amiens, France. Electronic address: firstname.lastname@example.org.
The appearance of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) after kidney transplantation is independently associated with poor long-term allograft outcomes. The objective of the present study was to evaluate the predictive value of a flow cytometry crossmatching (FC-XM) assay after the appearance of dnDSAs related to antibody-mediated allograft rejection (ABMR) after kidney transplantation.
MATERIALS AND METHODS:
A total of 89 recipients with dnDSAs after transplantation were included. The crossmatching results were compared with the dnDSA profile (the mean fluorescence intensity (MFI), the complement-binding activity, and the IgG subclass profile) and the biopsy's morphological features.
Of the 89 patients, 59 (66%) were positive in an FC-XM assay, 17 (19%) had complement-binding DSAs, 55 (62%) were positive for IgG1 and/or IgG3 in a solid phase assay, and 45 (51%) had morphological biopsy features linked to ABMR.
An FC-XM assay was unable to discriminate between cases with or without ABMR on biopsy findings; it had a low positive predictive value (<70%) and a low negative positive predictive value (<42.9%), taking into account the sensitivity of our assay (limit of detection: DSAs with an MFI >3000). In this context, the height of the MFI of the dnDSAs might be enough for a high positive predictive value for ABMR and additional testing for complement binding activity can remain optional.
Transpl Immunol. 2020 May 5:101303. doi: 10.1016/j.trim.2020.101303
Rejection in the setting of non-HLA antibody: new tools for navigating Bench to Bedside.
1 Department of Surgery, Duke University, Durham, USA.
2 Department of Pathology, Duke University, Durham, USA.
There is a growing body of literature linking non-HLA antibodies to acute and chronic allograft injury across all transplanted organ types (1). Even more striking is the injury potential observed when non-HLA antibodies are detected simultaneously with donor-specific HLA antibodies (2). The vascular endothelium serves as the primary barrier between the patient's immune system and the transplanted allograft; therefore, understanding how bound antibodies affect endothelial cells (EC) has been a long-standing topic of interest (Figure 1). EC dysfunction associated with non-HLA antibodies include hypercoagulability, activation and increased permeability, apoptosis, and in some cases complement activation (2, 3). The effector functions of non-HLA antibodies reflect intrinsic characteristics corresponding to titer, affinity, and isotype as well as extrinsic factors such as the non-HLA target antigen and its expression density within different allograft tissues. All of these factors contribute to the injury potential and the observed injury phenotypes associated with non-HLA antibodies. Therefore, we may need to rethink our definitions for antibody mediated rejection when facilitated by non-HLA antibodies, given that EC dysfunction and allograft injury may be mediated through mechanistic pathways that differ from HLA antibodies.
Am J Transplant. 2020 May 5. doi: 10.1111/ajt.15975.
HLA-specific memory B-cell detection in kidney transplantation: Insights and future challenges.
1 Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
2 Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.
Humoral alloimmunity mediated by anti-human leucocyte antigen (HLA) antibodies is a major challenge in kidney transplantation and impairs the longevity of the transplanted organ. The immunological risk of an individual patient is currently mainly assessed by detection of HLA antibodies in the serum, which are produced by long-lived bone marrow-residing plasma cells. However, humoral alloimmunity is complex, and alloreactive memory B cells constitute an additional factor in the interplay of immune cells. These recirculating "silent" cells are responsible for the immunological recall response by differentiating into antibody-producing cells upon antigen re-encounter. Historically, due to the lack of appropriate and routinely applicable assays to determine the presence and HLA specificity of alloreactive memory B cells, their contribution to the humoral alloimmune response has clinically often been suspected but could not be determined. In this review, we give an overview of recent advances in techniques to detect alloreactive memory B cells and discuss their strengths and limitations. Furthermore, we summarize experiences with these techniques in alloimmunized individuals and transplant recipients, thereby emphasizing unmet needs to be addressed in future studies.
Int J Immunogenet. 2020 May 10. doi: 10.1111/iji.12493.