On the role of HLA antibodies in hematopoietic stem cell transplantation

Abstract

While the role of donor-specific antibodies (DSA) in solid organ transplantation is well established, their importance in hematopoietic stem cell transplantation (HSCT) is only now becoming clear. A review of the literature reporting on HLA immunization in HSCT provides ample circumstantial evidence that donor-specific HLA antibodies (DSA) are associated with a 2- to 10-fold increase of graft failure of HLA mismatched HSCT, irrespective the type of the graft, or the patient conditioning. Nevertheless, this is not a condition 'sine qua non', and engraftment has been documented despite the presence of DSA. However, prediction of graft failure based on serology is cumbersome. Although sensitivity and specificity of current solid-phase assays (SPAs) for HLA antibody detection are high, correlation with graft failure remains elusive. When lacking an alternative donor, reduction of strong reacting DSA must be attempted. Unfortunately, results of DSA reduction treatments in HSCT are scarcely reported. Case reports show that persisting DSA after plasma-exchange and immunosuppressive treatment can become negative after a 'last rescue' in vivo absorption with antigen-bearing platelets or donor lymphocyte transfusions. The destruction of engrafting hematopoietic cells by antibodies appears to be an immediate event. Blocking antibody mediated effector functions, e.g. with intravenous immunoglobulin (IvIg), may have additional value, despite IvIg often not reducing the antibody titre. An even less explored aspect of HLA-immunization is the presence of non-DSA antibodies in the host or HLA antibodies emerging post-transplantation. Such antibodies, either causally or as confounders, may be associated with negative transplant outcome. We conclude that HLA antibody assessment should be at the forefront in the treatment handbook of HSCT.

Luminex® and Its Applications for Solid Organ Transplantation, Hematopoietic Stem Cell Transplantation, and Transfusion^*

“…The tremendous increase in the number of mismatched HSCT in recent years - including the unparalleled boost of cord blood units - is accompanied by the use of reduced intensive pretransplantation conditioning (RIC) regimens, as very recently shown by Brand et al [39]. Although this approach has led to a shift in the clinical paradigm stressing the necessity of HLA antibody detection and the performance of pretransplant cross-matches, the realization in clinical practice has not yet been accomplished.…”

“…The authors show a detrimental effect of DSA on graft failure as detected by a positive CDC cross-match. Nevertheless, even antibodies solely identified by standard Luminex technology that were not able to fix or deposit complement have been shown to be a risk factor for the outcome of HSCT [39]. It is worth mentioning that especially antibodies directed against HLA-DP antigens, which can reliably be detected only by Luminex SAB, could be associated with an increase in graft rejection (up to 38% in a cohort of 20 patients harboring exclusively HLA-DP antibodies).…”

Clinical Role of Human Leukocyte Antigen in Health and Disease

“…It is obvious that progress calls for registration and collaboration to resolve confusion around test results. For this aim, the assessment of HLA antibodies should be included in HSCT management protocols [115].…”

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection

“…With improvement in anti-HLA Ab detection techniques, HLA allele-specific Abs are now distinguishable by highly sensitive bead-based assays. 40 The results of this study clearly show that the allele-level DSA had direct cytolytic activity and impaired colony growth by unrelated BMMNC in vitro.…”