Desensitization Strategies for Donor-Specific Antibodies in HLA-Mismatched Stem Cell Transplantation Recipients: What We Know and What We Do Not Know

Abstract

In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application.

Keywords: Allogeneic stem cell transplantation; Desensitization; Donor-specific antibody; Graft failure.

Fig. 1

The pathogenesis of graft failure by DSAs after HLA-mismatched allogeneic HSCT. APCs display HLA antigens to naïve CD4⁺ T cells and then promote their differentiation into T follicular (Tfh) cells in the germinal center. Tfh cells facilitate the differentiation of activated B cells into memory B cells, plasmablasts, and plasma cells that produce DSAs. High-affinity DSAs, or rather, complement-activating DSAs, activate NK cells through the FCGR and stimulate them to release effector cytokines, which can enhance the cytotoxicity of nearby monocytes and increase damage through ADCC. In addition, activated monocytes release cytokines to facilitate the recruitment of additional NK cells. DSAs can also activate the classical complement cascade, leading to the formation of the membrane attack complex (MAC) C5b–C9. This causes the lysis of hematopoietic progenitor/stem cells and supporting cells, such as endothelial cells (ECs) and mesenchymal stem cells (MSCs), which facilitates graft rejection or poor graft function