HLA-specific memory B-cell detection in kidney transplantation: Insights and future challenges

Abstract

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.

Keywords: HLA antibodies; antibody-mediated rejection; donor-specific antibodies; humoral alloimmune response; kidney transplantation; memory B cells; single-antigen bead assay.

Figure 1

HLA‐specific memory B‐cell assays. HLA‐specific memory B cells can be detected by (i) tetramer analysis taking advantage of B‐cell receptors to be able to bind synthetic HLA molecules (upper row), (ii) culture supernatant analysis based on the ability of B cells to produce antibodies upon in vitro polyclonal activation (middle row) and (iii) ELISpot assays using either synthetic or donor‐derived HLA molecules performed by combining both of the aforementioned properties of B cells (lower row)